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Epigentica avanando nanomedicina

personalizado na terapia do cncer


Liu shujun um, *
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A verso final do publisher editada deste artigo est dispon!vel em adv deliv drogas rev
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Abstract
A medicina personali$ada tem como objetivo oferecer o medicamento certo para o paciente certo,
na hora certa% &le 'ferece oportunidades (nicas para integrar novas tecnologias e conceitos para a
doena progn)stico, diagn)stico e terap*utica% &n+uanto ,erapias personali$adas seletivos so
conceitualmente impressionante, a maioria das terapias de c-ncer t*m desfecho triste% ,al .alha
terap*utica pode resultar da falta de resposta, a resist*ncia aos medicamentos, recidiva da doena ou
efeito colateral grave de entrega da droga impr)pria% /anomedicina, a aplicao da nanotecnologia
na medicina, tem um potencial para fa$er avanar a identificao de biomarcadores de diagn)stico e
progn)stico ea entrega de droga direito de s!tios da doena% Aberraes &pigen0ticas contribuir
dinamicamente para a patog*nese do c-ncer% 1adas As caracter!sticas individuali$adas de
biomarcadores epigen0ticos, consideraes epigen0ticas iria aperfeioar significativamente
nanomedicina personali$ado% &sta 2eviso tem como objetivo dissecar a interface da medicina
personali$ada com nanomedicina e epigen0tica% 3ou 1escrever o progresso e destacar os desafios e
as reas +ue podem ser mais e4plorados aperfeioar os cuidados de sa(de personali$ados%
Palavras-chave: epigen0tica, biomarcadores, terapia5alvo, a nanotecnologia, as nanopart!culas,
distribuio de medicamentos, medicina personali$ada, nanomedicina, nanomedicina personali$ado
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1 introduo
6por e4emplo, mudanas epigenetic metila789es adn e modificaes de histonas: so o padro
hereditrio de alterao na cromatina e conse+uentemente, os genes ; < =% &mbora /o haja um
impacto sobre se+>*ncias de genes, modificaes epigen0ticas pode especificar padres de
e4presso g*nica em toda a diferenciao e desenvolvimento% "raas ? cooperao de c)digos
epigen0ticos e gen0ticos, um (nico )vulo fertili$ado com um conjunto de material gen0tico pode
desenvolver com preciso em sistemas biol)gicos comple4os, como os tecidos e )rgos com
morfologia e funes distintas% ' @apel crucial do crosstalA gen0tico5epigen0tica em fisiologia e
patologia 0 tamb0m evidente pelos seguintes factores5chave%'s "*meos mono$ig)ticos 6m$:
g*meos e4ibir grandes diferenas no desenvolvimento de doenas +uando eles crescem
separadamente, e potencial de tal doena 0 atenuado drasticamente +uando vivem em ambiente
semelhante ; B =% Al0m 1isso, CC,CD do genoma humano 0 id*ntica entre as pessoas individuais
com apenas E,<D de singularidade 6 http#FFGGG%ornl%govFsciFtechresourcesFhumanHgenome :% A
Interaco deste material gen0tico (nico de E,<D, juntamente com modificaes epigen0tica gera
vasta diversidade da populao humana% &m Alguns casos, +uando o e+uil!brio fisiol)gico 0
+uebrado por aberraes gen0ticas e F ou epigen0tica, resulta em doenas humanas 6por e4emplo,
leses cancerosas sist0micos:%
,radicionalmente, os pacientes so tratados por um Ione5si$e5fits5allI abordagem dentro de um
protocolo padro% As 1ecises de tratamento so principalmente decidiu baseando5se no estgio
cl!nico da doena e hist)rico m0dico e familiar do paciente, mas ignorando a biologia do indiv!duo
a conduo de tais doenas ; J =% &mbora &ssas abordagens fe$ alcanar notvel eficcia terap*utica
na cura de certos tipos de c-ncer 6por e4emplo, c-ncer testicular, e leucemias peditricas: ; K =, a
ta4a de sobrevida global de pacientes com c-ncer tem melhorado pouco nas (ltimas d0cadas,
defendendo a necessidade de novas id0ias e estrat0gias na gesto da doena% A /ova deciso de
tratamento deve integrar biologia doena abrangente, reagentes terap*uticas ade+uadas e ve!culo de
entrega de drogas em outros atributos pessoais 6idade, se4o, nutrio, condies psicol)gicas e
intestino microbioma ; L 5 M =:% &ssa Integrao trou4e o conceito de medicina personali$ada +ue
aborda o medicamento certo para a pessoa certa no momento certo%
A medicina personali$ada enfati$a a unicidade de uma pessoa, uma doena e um medicamento em
pontos de tempo espec!ficos em +ue prestar cuidados de sa(de individuali$ado para pacientes com o
m4imo de eficcia terap*utica no custo dos efeitos adversos m!nimos% A Nedicina personali$ada
tem sido amplamente e com sucesso aplicado O gesto de numerosas doenas humanas,
especialmente c-nceres% ' Nelhor e4emplo da terapia do c-ncer personali$ado vem da identificao
e testes cl!nicos do receptor de estrog*nio 6er: no c-ncer de mama e bcr F abl em cml% Apesar 1os
impressionantes benef!cios cl!nicos da sa(de individuali$ado, as +uimioterapias atuais ainda t*m
resultados desanimadores% /esses Pasos, a melhor caracteri$ao da doena utili$ando
biomarcadores apropriados 6por e4emplo, alteraes gen0ticas e epigen0ticas: pode ajudar os
m0dicos a decidir o melhor meio para entregar a droga a fim de proporcionar a eficcia
m4ima% &ntre Nuitos biomarcadores, modificadores epigen0ticos so os jogadores mais
importantes na concepo da medicina personali$ada, por+ue esses marcadores esto fortemente
correlacionados com atributos individuali$ados% Al0m 1isso, as barreiras +ue contribuem para o
fracasso +uimioterpico atual poderia ser secundria a entrega da droga abai4o do ideal% Pomo ,al,
a nanomedicina conseguiu superar essas armadilhas enviando especificamente as drogas para o
lugar certo, com to4icidade sist*mica provavelmente redu$ida% /ova /anotecnologia 6reagentes e
dispositivos por e4emplo nano5imagem: tamb0m pode ajudar na descoberta de novos
biomarcadores dos materiais limitados de forma no5invasiva, promovendo assim a sa(de
individuali$ado% @ara ' efeito, o verdadeiro sentido da medicina personali$ada deve ser as
integraes sem costura da medicina, a nanotecnologia e atributos pessoais, com considerao
epigen0tica colocado no local central% Pertamente /anomedicina personali$ado ser teoricamente
ben0fico para todos os tipos de pacientes, mas este artigo enfati$a, principalmente, suas influ*ncias
sobre a gesto do c-ncer, uma ve$ +ue o c-ncer 0 as leses representativamente sist*micas +ue so
as doenas mais letais em todo o mundo%
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2 a medicina personalizada no tratamento do cancro
2.1. Conceito e medicina personalizada
Pada pessoa 0 verdadeiramente (nico, e por isso so as leses cancerosas% Qingularidade 1e cada
pessoa inclui informaes cl!nicas, genRmica e ambiental, bem como a nature$a das doenas,
incluindo o seu in!cio, o curso de progresso e resposta ao tratamento% &ssa Qingularidade deve ser
usado para orientar o manejo da doena% A Nedicina personali$ada 0 individuali$ado ou baseados
em terapia individual, +ue leva em conta os perfis e4clusivos de um (nico paciente e uma (nica
doena% Pom A descoberta de marcadores gen0ticos, genRmicos e cl!nicos, medicina personali$ada
permite prever com preciso a susceptibilidade de uma pessoa de desenvolver a doena, a
progresso da doena, a resposta do paciente O terapia, e ma4imi$ar o !ndice terap*utico para o
tratamento ou cura de doenas com o m!nimo de to4icidade para um paciente espec!fico ; S , C =%
A medicina personali$ada tamb0m re+uer a integrao de outros fatores fisiol)gicos individuais, tais
como idade, raa, se4o, ambiente de vida, nutrio, herana gen0tica, metabolismo de drogas e
condies de sa(de nas decises terap*uticas% A Ttili$ao dessa terapia O base de marcador
espec!fico pode evitar a to4icidade e custos desnecessrios associados a medicao% @or &4emplo, a
maior ta4a de metabolismo de drogas indica a eliminao rpida de droga da circulao sist0mica, e
re+uer a infuso cont!nua para a manuteno da concentrao plasmtica terap*utica nesses
doentes% Nesmo Pom a semelhana do metabolismo do frmaco intr!nseca, a dose da droga pode
necessitar de ser alterada de acordo com a microbiota intestinal IpessoalI, o +ual foi recentemente
mostrado para afectar significativamente a eficcia terap*utica ; L 5 M =% 'utros &4emplos v*m de
pacientes com c-ncer, onde biomarcadores individuais se tornam importantes para permitir +ue os
m0dicos a tomar decises e fornecer atendimento mais personali$ado a um paciente
espec!fico% Pomo Tm e4emplo, as classificaes de pacientes de cancro do pulmo em pulmo de
c0lulas no pe+uenas e carcinoma do pulmo de c0lulas pe+uenas, no so suficientes para
determinar o melhor tratamento% 's N0dicos esto levando em conta essas caracter!sticas da
doena# tamanho do tumor, histologia, classificao, presena ou aus*ncia de metstases O dist-ncia,
al0m de idade e tabagismo hist)ria dos pacientes, e estado de mutao do gene 6por e4emplo, Aras,
egfr:% ,ais Abordagens individuali$adas com foco em novas terapias direcionadas podem assumir as
Ione5si$e5fits5allI protocolo padro para o tratamento de muitos outros tipos de c-ncer ; <E =% 's
&feitos promissores de tratamento personali$ado do c-ncer tamb0m so evidentes pela identificao
e testes cl!nicos do receptor de estrog*nio 6er:, pr e herB no c-ncer de mama% Perca 1e J<D dos
pacientes aumentou em L anos a sobrevida global em pacientes com er5positivo, no entanto, no
houve resultados significativos foram alcanados favoritos do tamo4ifeno no c-ncer de mama er5
negativo% Al0m 1isso, os benef!cios da medicina personali$ada, tem sido evidenciada em outras
doenas humanas, incluindo dist(rbios neuropsi+uitricos, doenas cardiovasculares, doenas
neurodegenerativas, diabetes e obesidade%/o "eral, o desempenho da medicina personali$ada
ajudar a tomar decises mais informadas e m0dicos ade+uados, e4ecute poss!vel interveno
precoce por doena deteco rpida, minimi$ar os custos de to4icidade e de sa(de, oferecendo
plano de tratamento preciso e evitar medicao desnecessria, prever e monitorar a progresso da
doena, assim alcanar maior probabilidade de resultados desejveis%
2.2. !ncologia Personalizada
A aplicao de Imedicina personali$adaI na terapia do c-ncer 0 chamado de Ioncologia
personali$adaI%,endo &m conta a diversidade de c0lulas tumorais e de cancro individuais 0 um dos
componentes mais importantes para o desenvolvimento de oncologia personali$ada% P-ncer
Tltrapassa as doenas cardiovasculares como o n(mero de uma das causas de morte em todo o
mundo% Nais 1e <%LEE pessoas morreram de todas as formas de c-ncer a cada dia nos eua em BE<E
; << =% A Ueterogeneidade do tumor 0 o maior cesto para reali$ar o diagn)stico e tratamento efica$
do cancro, embora muitos factores +ue contribuem para o insucesso da +uimioterapia% ' &spectro
de massa de tipos de tumores dentro de um dado cancro e a discrep-ncia c0lula5a5c0lula, foram
descobertos no interior dos tumores ; <B =% 's P-nceres +ue apresentam mesmo clinicamente como
o mesmo tipo ou subtipo poderia ser muito d!spares a n!vel molecular e, portanto, agir claramente
em resposta a intervenes terap*uticas ; <J , <K =% Al0m 1isso, alguns tumores primrios
individuais conter subpopulaes de c0lulas de c-ncer pe+uenos 6por e4emplo, c0lulas5tronco
cancerosas: +ue variam em capacidade metasttica e resposta ao tratamento% As P0lulas cancerosas
nos tecidos do tumor e do sistema de circulao pode e4ibir a capacidade de resposta diferente para
terapias% &specificamente, o c-ncer de mama, c-ncer de pulmo e c-ncer de c)lon representam
vrias entidades diversas doenas com variaes gen0ticas e epigen0ticas% Uansen et Al identificado
c-ncer de regies espec!ficas metilado5dna 6cdmrs: c-ncer de distino dos tecidos normais em
c-ncer de c)lon, e recentemente eles apresentaram variao de metilao estocstica dos mesmos
cdmrs no c)lon, pulmo, mama, tumores e adenomas ;Gilms <L =% ,homas et Al aplicada de alto
rendimento genotipagem para interrogar BJS conhecidas mutaes de oncogenes em todo <EEE
amostras de tumores humanos, e observou5se um n(mero inesperadamente elevado de co5
ocorr*ncia de mutaes ; <V =% Qtephens et Alevidenciado vrios tipos de rearranjos somticas em
genomas do c-ncer de mama humano, destacando o seu potencial contributo para a patog*nese do
c-ncer ; <M =% &ssa Ueterogeneidade c-ncer bem e4plica por +ue no 0 realista para desenvolver
IblocA5busterI drogas contra o c-ncer +ue curam todos os pacientes com uma determinada doena,
e tamb0m e4ige +ue as +uimioterapias efica$es devem ser entregues, no s) ao n!vel individual do
paciente e da doena, mas tamb0m um tumor ou espec!fico de c0lulas de tumor, os pontos centrais
de medicina personali$ada%
2.". #iomar$ers %ornecer as orienta&es 'undamentais para a medicina
personalizada
Assinaturas moleculares ou biomarcadores de tumor ou c0lulas de tumor so indicadores de
tumorig0nese, +ue 0 determinado principalmente pela interaco ou a coordenao de diversas vias
de sinali$ao e um resultado combinado da tumoral, do estroma e factores inflamat)rios do tumor
heterog0nea original% 's Wiomarcadores moleculares incluem genes mutantes, rnas, prote!nas,
lip!dios, carboidratos e pe+uenas mol0culas de metabolito, cujos n!veis de e4presso so positiva ou
negativamente correlacionada com comportamentos biol)gicos ou resultados
cl!nicos% Wiomarcadores Pl!nicos abrangem biomarcadores de diagn)stico indicando a presena ou
aus*ncia de uma doena, e de progn)stico e terapia de otimi$ao de biomarcadores +ue indicam as
caracter!sticas do paciente e doenas +ue influenciam planos de tratamento%,odos &sses
biomarcadores so as IbandeirasI para entregar o verdadeiro sentido dos cuidados de sa(de
individual% &les @odem ser utili$ados separadamente, mas a melhor prtica 0 a aplicao de
biomarcadores abrangentes e imparciais simultaneamente para fa$er os es+uemas terap*uticos mais
ade+uados para um determinado paciente%
2.".1. (normalidades Cromoss)micas
As anormalidades cromossRmicas podem aparecer +uando os cromossomos +uebrar e os
fragmentos de mudar para outros cromossomos% &stes @ontos de +uebra causar a perda de materiais
gen0ticos ou a alterao do microambiente do gene ou a gerao de novos genes de fuso% A
Paracteri$ao de translocaes espec!ficas do paciente revolucionou o tratamento personali$ado do
c-ncer% @or &4emplo, muitos tipos estruturalmente diferentes de anomalias cromossRmicas foram
definidos na leucemia, incluindo t 6<L, <M: 6+B<X +<B: 5 pml F rara, t 6<<X <M: 6+BJX +<B: 5 p$lf F rara ,
t 6SX B<: 6+BBX +BB: 5 aml< F eto, t 6SX <V: 6p<<X p<J: 5 cbp F mo$, t 6<<, BJ: 6+BJX +<J: 5 mll F pJEE, e
inv 6<V: 5 cbfY F smmhc% &stas .uses gen0ticas alterar a funo biol)gica dos genes originais, tais
como a afinidade de ligao a dna ou a interaco f!sica com outros parceiros de transcrio, como
aml< F eto interage com dnmt< F hdac<, em ve$ de hat, para suprimir a e4presso do gene alvo de il-
3 ; <S =% 'utro &4emplo 0 famoso gene de fuso bcr F abl, +ue 0 derivada a partir do rearranjo da
regio de agrupamento de ponto de interrupo 6bcr: no cromossoma BB com o proto5oncogene c5
abl no cromossoma C gene de fuso bcr F abl est presente em praticamente todas as cml 6Z CLD dos
casos: ; <C = e algumas todos ; BE = pacientes e produ$ hyperactivated sinali$ao +uinase
impulsionado5abl% Qeus Inibidores 6por e4emplo imatinib: ter reali$ado eficcia terap*utica
marcante em pacientes com lmc, o +ue representa uma das performances mais frut!feras de
segmentao biomarcadores de translocao na terapia do c-ncer%
2.".2. *uta&es +enticas
1ois tipos principais de genes envolvidos na patog0nese do cancro so os oncogenes e os genes
supressores de tumor 6etg:% &n+uanto A maioria das mutaes gen0ticas no implicar fen)tipos da
doena, leses cancerosas comeam +uando as c0lulas acumulam erros gen0ticos e multiplicar
ilimitadamente% &," Pom mutaes ad+uiridas foram avaliadas em vrios cancros, como o pulmo,
colo5rectal, cancro da mama e leucemia% @or &4emplo, as alteraes do gene tpLJ foram observados
em mais de LED dos tumores malignos humanos% &mbora Nuito crucial para o crescimento de
c0lulas normais, vrios proto5oncogenes, +uando mutado, 0 hiper5activados levando a patog0nese
do cancro% A 1escoberta de mutaes causadoras de doenas em uma fam!lia pode prever os
indiv!duos Ide riscoI se eles so suscet!veis a c-ncer ou outras doenas ; B< = e como eles iro
resposta a certos medicamentos, levando, assim, a terapia individuali$ada% As Nutaes de alguns
oncogenes conhecidos incluem methyltransferases dna 6dnmtJa ; BB =, dnmt< ; B< , BJ =:, prote!nas
+uinases 6por e4emplo, egfr, Ait e fltJ, erbbB: e gtpase 6por e4emplo Aras:% As Identificaes de Ait e
mutaes fltJ, bem como a aplicao de seus inibidores espec!ficos para os pacientes em +uesto
tenham avanado o c-ncer de gesto personali$ada% /as Pl!nicas, mutao Ait espec!fico no c)don
SBB pode predi$er a resposta ao imatinibe, en+uanto mutaes no c)don S<V no so e podem ser
direcionados com sucesso com midostaurina ou dasatinib ; BK =% Nutaes &spec!ficas no gene egfr
como preditores de resposta ao erlotinib ou gefitinob 0 o primeiro e4emplo do uso de
biomarcadores para prever a resposta de agentes direcionados ; BL =% Al0m 1isso, cada ve$ mais
provas demonstra a induo no espec!fica de mutaes do gene por +uimioterapia% A 1escoberta
de mutaes gen0ticas indu$idas por +uimioterapia pode ajudar a desenvolver inibidores especiais e
tamb0m prever como os pacientes a administrar ir resposta aos medicamentos selecionados ; BL =,
um importante conceito de medicina personali$ada% @ara &ste fim, todos os tratamentos e terapias
so adaptados para alvejar o (nico espectro de mutaes +ue definem os tumores individuais e
subpopulaes de c0lulas de tumor ; <B , BV 5 BS =%
2.".". Polimor'ismos e nucleot,deo -nico .snps/
3ariaes de nucleot!deo (nico 6snps: ocorrer em um local espec!fico na codificao e regies do
dna genRmico no codificante% Q/@s &sto ocorrendo a cada <EE a JEE pares de bases ao longo do
genoma humano e +ue compem cerca de CED de toda a variao gen0tica humana% /as [ltimas
duas d0cadas, mais de <E milhes de snps foram descobertos ; BC =%&n+uanto A maioria dos snps
no t*m impactos )bvios sobre processos biol)gicos cr!ticos, alguns deles implicam fen)tipos da
doena ou afetar a resposta dos pacientes ao medicamento representando assim biomarcadores
favorveis para o diagn)stico e progn)stico% @or &4emplo, irinotecano 0 uma forma de
+uimioterapia para tratamento de pacientes com carcinoma de c)lon% Tm Netabolismo irinotecano
(nico snp governante pode prever se este subgrupo respostas dos pacientes ao tratamento com
irinotecano% Q/@s &m genes brca< e tpLJ associar com risco aumentado para c-ncer de mama,
en+uanto outros snps, como rsBJLBEBS no cromossomo <J+J<%J, indicam maior suscetibilidade
para c-ncer de pulmo em no5fumantes ; JE =% 'utro &4emplo 0 a nature$a polim)rfica do
citocromo pKLE 6cyp: genes, incluindo o n(mero de c)pias 6cnv: variantes, mutaes, inseres e
delees, +ue afetam significativamente a resposta de drogas individual% Assim, o emprego de cyp
biomarcadores polimorfismo em cl!nicas pode melhorar a resposta de drogas e diminuir os custos
de tratamento ; J< =%
2ecentemente snps foram identificados em mircorna 6mir: genes, a sua ma+uinaria de
processamento e os locais de ligao ao alvo, +ue funcionam como um outro indicador de risco para
o cancro, o progn)stico do paciente e eficcia do tratamento% mirs so rna no5codificante
reguladora de \ BB nucle)tidos +ue regulam a e4presso do gene atrav0s da hibridao com o arnm
L]utr ou J]utr, ou mesmo a regio de codificao ; JB =% &4presso Nir anormal provoca vrias
doenas humanas e mir e4presso assinaturas podem classificar e4clusivamente tipos de c-ncer
; JJ =% Q/@s 1e mirs poderia modular significativamente suas atividades biol)gicas representando
assim biomarcadores atraentes para a tomada de decises cl!nicas%/o "eral, 0 cada ve$ mais claro
+ue snps ser um facilitador importante para projetar e desenvolver medicina personali$ada% @or
Pausa do potencial cl!nico do snps, vrios grupos, como o dos estados unidos projeto genoma
humano 6hgp: e snp consortium, esto a criao de mapas de snp do genoma humano, a fim de
identificar biomarcadores de progn)stico e diagn)stico (teis% ^nome &st fornecendo
se+uenciamento do genoma completo para os consumidores +ue procuram um perfil gen0tico
individual ;JK =% 'utras &mpresas 6BJandme, decode genetics e navigenics: esto utili$ando matri$
snp de alta densidade para dissecar a informao gen0tica de um indiv!duo% Atualmente IBJandmeI
pode determinar snps de uma pessoa por menos de um d0cimo do custo, +uando comparado ao
genoma se+>enciamento%/o &ntanto, a maior barreira para a aplicao cl!nica snp em medicina
individuali$ada 0 a Idiscriminao gen0ticaI a +uesto%
2.".0. Clulas Circulantes de dna1 rna e tumorais
/o nosso sistema o sangue circula vrios tipos de arn e de adn, na forma de livre ou envoltos em
gl)bulos vermelhos e pla+uetas ou nucleossomas% &stes 'ligos so liberados por apoptose e c0lulas
mortas ou c-ncer e c0lulas regulares como mensageiros, +ue 0 evidente pela funo de
transformao destes oligos de pacientes com c-ncer% 1/A Pirculante foi demonstrado pela
primeira ve$ no sangue humano de doadores saudveis, mulheres grvidas e pacientes cl!nicos em
<CKE, mas nenhum interesse foi desenvolvido at0 n!veis elevados de dna foram encontrados no
sangue de pacientes com l(pus eritematoso sist*mico e tamb0m c-ncer% &stes Adn podem ser
utili$ados 6a: como um marcador precoce para a deteco do cancro, devido ao seu n!vel elevado e
6b: para a monitorao da eficcia terap*utica +uando os seus n!veis de volta ao normal%
Nirs pode ativar ; JL = ou reprimir a e4presso do gene alvo e so a maior classe de genes
reguladores% /o Qangue circulante, e4presso diferencial de mirs entre as pessoas normais e
pacientes tem sido evidenciada% @or &4emplo, o n!vel de mir-155, mir-210 e mir-21 no soro de
pacientes com linfoma de c0lulas b ]0 elevada ; JV =% Nitchell et Al relataram +ue os n!veis s0ricos
de mir-141 pode distinguir pacientes com c-ncer de pr)stata a partir de controles saudveis
; JM =% &stes Nirs circulam esto emergindo como importantes marcadores no5invasivos 6revisto
em ; JS =:, o +ue pode beneficiar o diagn)stico e progn)stico, mesmo funcionam como uma
bandeira para a eficcia terap*utica% Al0m 1isso, na corrente sangu!nea circula c0lulas tumorais,
+ue so derivados a partir de um tumor primrio, com o potencial para crescer em outra parte do
corpo% ,ais P0lulas cancerosas circulantes 6ctcs: podem fornecer aos m0dicos uma maneira mais
avanada no5invasivo para descobrir o estgio da metstase do c-ncer, as abordagens
individuali$adas para pacientes, ea maneira de monitorar o progresso da doena% &m "eral, os
marcadores acima mencionados 6adn, arn, e mir ctc:, so distintas entre o cancro e as c0lulas
normais, mesmo as c0lulas cancerosas em diferentes estdios de progresso da doena% ,ais
Wiomarcadores diversificadas oferecer uma plataforma crucial para compreender a etiologia e
patologia dos cancros com um forte apoio para a medicina personali$ada%
2.".2. 34micas3 dados o'erecem as in'orma&es mais a5rangentes para a concepo da
medicina personalizada
&mbora as identificaes das mutaes da prote!na +uinase levaram O terapia5alvo frut!fera, a ta4a
de sobreviv*ncia de pacientes com c-ncer aumentou pouco mais de d0cadas% &stes ,radicional in
vivo e ensaios in vitro so capa$es de medir apenas alguns par-metros na melhor das hip)teses,
proporcionando assim um mero instant-neo dos poss!veis efeitos de uma determinada droga% @ara
Quperar essa alta ta4a de fracasso de drogas, o +ue precisamos 0 o cuidado terap*utico
personali$ado com base em biomarcadores gen0ticos e epigen0ticos abrangentes, +ue s) pode ser
descoberto com sucesso por I5)micasI, incluindo genRmica, transcriptRmica, proteRmica,
metabolRmica e epigenomics, atrav0s a utili$ao de tecnologias de alto rendimento 6por e4emplo,
o se+>enciamento de alto rendimento em uma escala do genoma ; JC =:%I_micasI tecnologias
podem descobrir e caracteri$ar as c0lulas tumorais, tumores e biomarcadores espec!ficos da pessoa
+ue permitam o avano da terapia individuali$ada ; KE =% 2ecentemente, feinberg et al e4ecutar a
anlise do genoma escala imparcial de \ K milhes de sites cpg entre MK indiv!duos com teste
abrangente metilao em relao O base de matri$, e encontrou BBM regies mostrando enorme
variabilidade inter5individual 6regies variavelmente metiladas, vmrs: em todo o genoma % Netade
1estes vmrs eram estveis entre os indiv!duos com mais de uma m0dia de << anos e estes vmrs
definido um perfil epigenRmico personali$ado ; K< =, +ue pode ser utili$ado como biomarcador de
diagn)stico em cuidados de sa(de individuali$ado% Al0m 1isso, a modulao espec!fica de vias
drogas oncog0nicos em subpopulaes de pacientes pode prever a resposta a terapia5alvo% @or
&4emplo, andersen et al utili$ou uma abordagem de f)sforo5profiling baseado em caminho para
identificar e +uantificar, os biomarcadores espec!ficos da droga clinicamente relevantes para
fosfatidilinositol J5+uinase 6piJA: inibidores da via% &les 1escobriram +ue M< de JML fosfopept!deos
no redundante piJA relevantes foram relacionadas com a droga e << deles por todos os inibidores
selecionados ; KB =% &stes Narcadores espec!ficos da droga pode ser utili$ada para o
desenvolvimento de terapias adaptados para os pacientes% Al0m 1isso, a anlise de +uatro colorectal
e dois c-nceres de mama com se+uenciamento paralelo em massa revelou uma m0dia de nove
se+>*ncias rearranjadas 6variao K5<L: por tumor ; KJ =, indicando +ue o e4ame da e4clusividade
de um (nico tumor 0 fundamental para a medicina personali$ada sucesso %
/o entanto, a aplicao de dados prote)mica na terapia do c-ncer personali$ado 0 muito
desafiador%&n+uanto /umerosos IRmicasI dados foram gerados a partir de amostras de pacientes e
linhas celulares e de alta +ualidade IRmicasI de dados, +ue podem produ$ir resultados
significativos, faltam ; J =% As Pondies fisiol)gicas em tumores e as pessoas so din-micas e
podem mudar ao longo do tempo% Nesmo As mais avanadas t0cnicas s) pode rende um snap shot
da doena, diminuindo assim o valor cl!nico da IRmicasI de dados% A Papacidade e os
procedimentos de interpretar IRmicasI dados tamb0m so discut!veis% @ortanto, muito poucos foram
tradu$idos do banco de cabeceira, embora muitos IRmicasI dados foram gerados% ` @or isso +ue,
em ve$ de usar IRmicasI de dados na tomada de deciso do tratamento, atualmente os m0dicos
preferem adotar biomarcadores IsimplesI, como a mutao +uinase, colorao ich, e4presso de
receptores hormonais e F ou aberraes cromossRmicas%
2.0. ! esa'io da medicina personalizada
,erapia personali$ada oferece grandes oportunidades para ma4imi$ar os benef!cios terap*uticos
alvejando as anomalias gen)micas ou epigenRmicos en+uanto minimi$am a to4icidade, ao mesmo
tempo, evitando o tratamento em no5respondedores% Apesar 1a con+uista impressionante no
tratamento do cancro, medicina personali$ada enfrenta in(meros desafios, incluindo a ta4a de
ine4plicvel alta fracasso de terapias5alvo e as dificuldades em descobrir e validar biomarcadores
; KK , KL =% A Nedicina personali$ada 0 tamb0m desafiado pelas dificuldades em +uantificar alguns
fatores pessoais 6por e4emplo, ambiente e condies psicol)gicas de estar:, Ias mil dolares
genomas, a anlise <EE mil d)laresI problema ; KV =, as formas de fornecer com preciso as drogas
aos locais de ao, a capacidade dissecar dois tumores morfologicamente id*nticas, bem como a
heterogeneidade e vrios processos biol)gicos, em tumores s)lidos, incluindo a angiog0nese,
microambiente tumoral e dorm*ncia% As Qolues para esses problemas iro certamente ajudar os
m0dicos a elaborar tratamentos espec!ficos para cada paciente baseando5se em assinaturas (nicas do
tumor do paciente em determinada fase de progresso da doena%
"o to#
". 6anotecnologia na medicina personalizada
".1. Conceito a nanomedicina
&n+uanto a mortalidade redu$iu recentemente devido ao entendimento avanado da etiologia do
c-ncer e da patologia, bem como os dispositivos de diagn)stico e tratamentos aperfeioados, o
c-ncer permanece doenas mais letais do mundo% Plassificaes 1e diagn)stico e progn)stico
atuais no refletem precisamente a heterogeneidade cl!nica de tumores e so insuficientes para fa$er
previses para os resultados dos pacientes ; KM 5 KC =% 's Atuais regimes dispon!veis para o
gerenciamento de c-ncer, incluindo cirurgia, radioterapia e medicamentos +uimioterpicos, so no5
seletivo com to4icidade inaceitvel% /o U janela terap*utica dispon!vel para sair mais benef!cios
para os pacientes +ue t*m alto risco de recidiva precoce ou multirresist*ncia avanada e
refratariedade% &nfrentar &sses desafios re+uer a identificao de agentes anti5c-ncer novas, e mais
importante, a seleo de portadores de administrao de medicamentos ade+uados 6por e4emplo,
nanopart!culas: conjugado com ligantes individuali$adas corretos ou biomarcadores de pacientes%
/anomedicine, referred by the national institutes of health, is the application of nanotechnology in
medicine% ,hese applications include the drug delivery, disease detection, diagnosis, and treatment%
,he disease areas include cancerous lesions ; LE =, cardiovascular system, lungs, blood,
neurological diseases, diabetes, inflammatoryFinfectious diseases, parAinson]s or al$heimer]s
disease, orthopaedic problems and so on% ,he types of nanoparticulates utili$ed are <: biological
mimetics and functionali$ed carbon tubes, B: nanofibers and polymeric nanoconstructs, J:
nanoscale microfabrication5based devices and silicon microchips for drug release, K: nanomachines
made from dna parts and dna scaffolds, and L: nanoscale particle technologies for delivering drug,
genetic materials and diagnostic agents ; L< =%
".2. 7herapeutic (pplication o' nanoparticles
/anocarriers are classified into passively and actively targeting particles% @assively targeting
nanocarriers accumulate in the tumor by enhanced permeability and retention effect% ,hese particles
Gere approved for clinical practice in <CSEs and marAeted in <CCEs% In contrast, actively targeting
nanocarriers are conjugated Gith molecules binding to antigens or receptors overe4pressed in tumor
cells% ,he individuali$ed biomarAers could enhance the specificity of targeted nanocarriers in a
given patients%
".2.1. 8ole o' nanoparticles in drug deliver9
In cancer chemotherapy, most drugs do not greatly differentiate cancerous cells from normal ones,
leading to systemic to4icity and adverse effects in other tissues, including bone marroG
suppression, cardiomyopathy and neuroto4icity% /o selection of drug targets significantly constrains
the ma4imal alloGable doses in vivo % /anoparticles can specifically transport comple4 cargoes to
the metastasis sites, such as lungs, liver and lymph nodes, and target specific cell populations Githin
these organs Ghen conjugated Gith disease or patient5relevant biomarAers ; LB =% ,o this end,
nanoparticles have been used to override several pitfalls of conventional drug delivery systems,
such as nonspecific biodistribution and targeting, lacA of Gater solubility, poor oral bioavailability,
and loG therapeutic inde4 Ghich influence both cancer and normal cells, limitation of the
achievable dose in tumor, strong serum binding affinity 6eg about SED of borti$omib binds to
plasma protein,http#FFGGG%drugs%comFppaFborte$omib%html : and faster clearance in the circulating
system% As chemo5drug delivery vehicles, nanocarriers can <: improve the therapeutic efficacy of
anti5cancer drugs, since the optimi$ed si$e and surface characteristics can increase their circulation
time in bloodstream, B: selectively deliver drugs to cancer cells in passive accumulation through
their enhanced permeability and retention effect, J: in active targeting, selectivity can be enhanced
by the conjugation of tumor specific ligands or antibodies, and K: overcome drug resistance through
escaping from p5glycoprotein, one member of adenosine La5triphosphate5binding cassette 6abc:
transporter family% As an e4ample, monoclonal antibody nanoparticles can enhance diagnosis and
cancer therapy by targeting drug to tumor specifically and sparing the surrounding normal tissues%
/anochannel electroporation is able to deliver Gell5defined amounts of materials 6eg mirs and
sirna: into a single living cell ; LJ =% bhile the application of this nanochannel electroporation is
still in vitro , it has great potential to target the small population of cancer stem cells in a given
tumor, the most difficulties in personali$ed cancer therapy%
".2.2. (pplication !' nanoparticles assists 5iomar$er discover9
/oGadays various nano5therapeutics have reached patients, including anticancer drugs and imaging
agents, but there are only feG clinically approved nanocarriers that incorporate molecules to
selectively bind and target cancer cells ; LK =% Individual biomarAers are the Aeys to successfully
develop and employ personali$ed therapies, because biomarAers are crucial to distinguish individual
patient or tumor tissue or even a single tumor cell at a given stage of disease development and
predict the clinical outcomes% It]s highly difficult to identify clinically meaningful biomarAers from
a given patient, specifically Gith barely available or detectable materials% In such cases, nano5
particulate systems may be very useful in uncovering prognostic and diagnostic marAers, detecting
circulating tumor cells, monitoring therapeutic efficacy in non5invasive Gay% .or e4ample, nano5
materials 6eg biocompatible and stable fluorescent silverFdendrimer nanocomposites: are suitable
for labeling cells in vitro. cuantum 1ots as molecular labels have potential to discover the earliest
signs of cancers% Pareful selection and design of nanoparticle surface can specifically condense a
subset of biomarAers ; LL , LV = and se+uester them for further investigations by high5sensitivity
domicse tests% /anobiosensors can improve cancer biomarAer discovery by sensitively detecting
multiproteins in various clinical samples ; LM=% Nagnetic nanoparticles can capture circulating
tumor cells in bloodstream ; LS = thereby promoting tumor detection% 'verall, Ge e4pect that, by
means of novel nanotechnology, the detection of sparse biomarAer Gill become true in vivo even
Ghen the tumor groGth is still undetectable by typical techni+ues%
".2.". 7he Challenge o' nanomedicine
Although nanomedicine has brought considerable advances in fighting cancer regarding to the
diagnosis, prognosis and therapeutics, it is still at the early stage of development and meets various
challenges% .or e4ample, there are no efficient Gays to determine the body distribution of
nanoparticulate carriers after system administration, and no suitable imaging modalities to vision
the biodistributions over time ; LC =, although radiological imaging can tracA and +uantify particle
distribution ; VE =% /anoparticles are to4ic to several organs ; V< f VV =, particularly those particles
Gith little solubility or no biodegradation at the accumulation location% 2egarding to the fda5
approved drug5containing nanoparticles, Ghile liposome5encapsulated do4orubicin has brought
striAing clinical benefits Gith reduced to4icity 6eg cardioto4icity:, its therapeutic efficacy against
the tested tumors Gas unsatisfactory% @4l remarAably increases the efficient of hydrophobic cancer
drug delivery, but there is no obvious enhancement in survival rate% ,here are multiple hurdles
contributing to such nanomedicine failure, but non5integration of individuali$ed factors 6drug
metabolism rate, epigenetic biomarAers, and tumor heterogeneity etc%: may speaA really loudly here%
".". (pplication !' nanotechnolog9 in personalized therap9
@ersonali$ation of cancer therapies relies on a better understanding of the disease at the molecular
level, including the mechanisms of cancer initiation and invasion, the identifications of prognostic
and diagnostic biomarAers as Gell as the development of novel therapeutic agents% /anotechnology
can create multi5functional platforms, Ghich advance the anti5cancer drug discovery and delivery,
the identification of individual domicse information ; VM =, and the monitoring of disease course and
treatment outcomes% UoGever, Githout combining nanotechnology Gith personali$ed attributes f
dpersonali$ed nanomedicinee, Ge Gould e4pect the chemotherapeutic failure to be continuously
arisen from such independent practice% ,he uni+ueness of nanoparticulates is their multi5
functionality% Wiotargeting ligands 6eg antibodies, peptides or small molecules:, imaging labels,
therapeutic drugs and others can be integrated into a single nanoplatform, Ghich can ma4imi$e the
therapeutics by specifically delivering drugs 6even drug cocAtails: to the action sites, identifying
diagnosisFprognosis biomarAers and monitoring disease progress after chemotherapy% Quch multi5
functional nanoplatform nicely fits the features of personali$ed therapy# early detection,
combination of diagnostics Gith therapeutics%
,o date, nanotechnologies have already brought benefits to the personali$ed treatment%
/anotechnology can efficiently and specifically deliver biological therapies, such as cells and genes
that come from a given patient% Qome nanoparticles and nanodevices 6eg nanobiosencors and
nanobiochips: have been conjugated Gith patient5specific ligands targeting special tumor cells to
improve clinical efficacy ; VS =, and such nanoparticle5based drug delivery plus the right dose and
time is re+uired by successful individuali$ed medicine ; VC =% Nolecular imaging is an important
basic technology for personali$ing health care% /ovel molecular imaging tools 6eg
superpapramagnetic contrast agent and perfluorocarbon nanoparticles: Gill enable non5invasive
characteri$ation of patients for delivering personali$ed therapy ; ME =% .or e4ample, gvYJ5targeted
paramagnetic nanoparticles have been used to noninvasively detect very small regions of
angiogenesis associated Gith nascent melanoma tumors ; M< = and deliver higher doses of drugs
directly to the tumor site Githout systemic to4icity% ,he aforementioned achievements offer
opportunities for the progression of personali$ed oncology in Ghich cancer detection, diagnosis and
therapy are tailored to each individual]s molecular signature thereby ma4imi$ing efficacy, but
sparing patients unnecessary to4icity%
"o to#
0. Potential role o' epigenetics in the design o' personalized
nanomedicine
0.1. Epigenetic eregulations cause human cancer
0.1.1. Concept !' epigenetics
"enetic alterations 6eg deletions and mutations: could lead to the abnormal signaling pathGays and
sometimes drive illnesses% ,his concept provides a sound rationale for pathGay5based drug
discovery, in Ghich the targeted therapy is built to against both mutant oncoproteins 6Ait, bcrFabl:
; MB f MK = and Gild5type effectors ; ML = residing upstream or doGnstream of the dysfunctional
pathGays% In contrast, epigenetics is dealing Gith the modifications of dna and proteins 6eg core
histones:% ,he term depigeneticse Gas first used by british biologist, conrad Gaddington, in <CLEs to
e4plain Ghy some dgenetice changes do not develop neG phenotypes, and hoG genes and their
environments cooperatively determine the phenotypes% ,oday epigenetics is referred to the heritable
patterns of changes in chromatin and gene e4pression, but no impact on dna bases ; < , MV =%
Although no change in genomic codes, epigenetic modifications 6eg dna methylation: are
inheritable throughout successive cell divisions and can even be passed onto the ne4t generation
; MM =% Aberrant epigenetics causes numerous human diseases, but these modifications are reversible
representing promising targets for therapeutic interventions% As such, epigenetics has become one of
the most attractive fields in the current biomedical research landscape since the inception of
epigenetics in the past century%
0.1.2. Environmental (nd intrinsic signals criticall9 in'luence epigenetics
bhat factors determine epigenetic balanceh It is reported that environmental and lifestyle5related
influences, such as nutrition, to4ins and drugs as Gell as e4posure to stress, can induce epigenetic
changes, indicative of epigenome as a biochemical record of relevant life events ; MV , MS f SE =%
Qpecial environment, liAe maternal epigenetics and maternal behavior, also impacts epigenetic
variations ; S< , SB =, Ghich is strongly supported by the observed aging5related epigenetic changes
; SJ , SK = and the discoveries shoGing that mono$ygotic tGins have greater differences in global
dna methylation in older than in younger% Quch divergence of epigenome in mono$ygotic tGins is
decreased Ghen they are living in similar environment ; B =% Qpecifically, the en$ymatic activities,
Ghich cataly$e histone modifications, are governed by environmental and intrinsic stimuli ; SL =%
Quch stimuli5induced histone modifications can remodel the chromatin and yield short5term orFand
long5term outcomes ; SV =%
/oticeably the change of environmental and intrinsic stimuli for a given person is fre+uent and
dynamic% ,he dynamic environments create the dynamic epigenetic modifications changing over
time, Ghich are demonstrated by the observation shoGing that an <<5year span of global dna
methylation alteration in participants of an icelandic cohort, and age5 and tissue5related changes in
some cpg islands from an array of <K<J arbitrarily chosen cpg sites near gene promoters ; SK , SM =%
,he dynamic cooperation of all epigenetic modifications remodels the chromatin structure in a
specific region to turn onFoff gene e4pression ; SS = at a given time and environment% Quch personal
environmentalFepigenetic influence should be incorporated into the treatment decisions in
personali$ed medical practice%
0.1.". Epigenetic Codes
&uAaryotic nucleosomes, consisting of a histone octamer 6tGo hBa, hBb, hJ and hK: Grapped by <KM
base pairs of dna fragment, are the fundamental repeating units of chromatin and carry
epigenetically inherited codes through covalently modified histones and dnas% &pigenetic codes
mainly have histone modifications and dna methylation% Qome studies ; SC f C< = also include
microrna, other non5coding rna and even nucleosome positioning, but i vieG these as upstream
regulators or doGnstream factors of epigenetics% Uistone modifications occur mainly on their n5
terminal tails, including acetylation, methylation, phosphorylation, sumoylation and ubi+uitination%
,he en$ymes involved are hats, hdacs, hmts, hdmts, Ainase, phosphatase, ubi+uitin ligases,
deubi+uitinase, sumo ligase, protease and so on ; CB , CJ =% Integration of all histone modifications
constitutes the dhistone codee, Ghich modulates diverse biological processes including gene
regulation, dna repair and chromosome remodeling% In contrast, dna methylation represents a
covalent chemical modification of dna Githout disruption of dna se+uence% In the presence of s5
adenosyl5methionine 6sam: that serves as a methyl donor, a methyl group is added to c5L position of
cytosine residues generating L5methylcytosine% 1na methylation critically influences 4 chromosome
inactivation, genome imprinting, transposons silencing and gene transcriptional regulation ; CK =%
UoGever, the e4pression profile of a given gene is the conse+uences of the dynamic cooperation
among dna methylation and histone modifications%
0.1.".1. (5errant hdac activities drive cancer
Among the numerous posttranscriptional modifications, acetylation and deacetylation are the most
e4tensively studied histone changes, and typically cataly$ed by hat and hdacs, respectively% In
general, histone deacetylation results in chromatin condensation Gith the conse+uence of gene
silencing, in contrast, histone acetylation leads to chromatin rela4ation and gene reactivation% In line
Gith these, abnormal hdac e4pression or activity has been shoGn to be the driving forces in the
development of human malignances ; CL =, because aberrant hdac activities could condense the
chromatin and silence tsgs, resulting in unlimited cancer cell proliferation%
'n the basis of se+uence identity and domain organi$ation, hdacs are classified into four classes
; CV =, class i 6hdac<, B, J and S:, class ii 6hdacK, L, V, M, C, <E:, hdac iii 6sirtuins in mammals, sirts:
and hdac iv 6hdac <<:% Plasses i, ii and iv are referred to as dclassicale hdacs representing promising
anti5cancer drug targets ; CL =% /oGadays there are numerous hdac inhibitors 6eg saha, valproic
acid, tsa etc%: being studied in vitro and in the clinics 6revieGed in ; CL =:% ,hese inhibitors blocA
hdac activities, remodel the chromatin and turn on the tsg e4pression, thereby leading to a broad
spectrum of anti5cancer activity% UoGever, the hdac inhibitor trials as monotherapy have shoGed
severe to4icities and failed to induce a long5term response% ,hese dismal outcomes could result
from the dynamic coordination of distinct histone modifications Gith dna methylation as Gell as the
cooperation of different histone modifications themselves, Ghich is a sound rationale for the
combination of hdac and dnmt inhibitors% Noreover, other contributors to the therapeutic failure of
hdac inhibitors could be the tumor heterogeneity, in Ghich the elevated e4pression of class i or ii
hdac isoforms associates Gith improved prognosis and predicts better clinical outcome in specific5
tumor entities ; CM =% As such, the effective strategies involving in hdac inhibitor trials should be to
pinpoint the most relevant hdac molecules in a given tumor from a specific patient and select the
appropriate compound for mono5 or combinational therapy, a concrete application of personali$ed
medicine%
0.1.".2. (5normal dna meth9lation in cancer
1na methylation is under control of dnmts, including dnmt<, dnmt<b, dnmtB, and dnmtJa and
dnmtJb ; CS =% Among those, dnmt< is the maintenance en$yme in dividing cells and preferentially
replicates already e4isting methylation patterns, but dnmtJa and Jb are de novo en$ymes
responsible for establishing de novo methylation% Although the mechanisms leading to dna
hypermethylation remain to be fully e4plored, accumulative evidence demonstrate that all dnmt
isoforms cooperatively determine dna methylation status ; CC f <E< =, since AnocAdoGn of one
isoform only did not cause the complete loss of methylation in mouse stem cell ; <EB = and colon
cancer ; <EJ =% .urther, mutations of dnmt< and dnmtJa have been found to reduce dnmt activities
; B< , BB =% Interestingly, ten5eleven5translocation 6tet: family, a fusion partner of the mll gene in
aml, has been found to play critical roles in determining dna methylation status ; <EK , <EL =% ,his
gene family has three members# tet<, tetB and tetJ, Ghich cataly$e the conversion of methylcytosine
6Lmc: to L5hydro4ymethylcytosine 6Lhmc:, and AnocAdoGn of tet< by sirna led to the decreased
Lhmc ; <EV =% It is also reported that isocitrate dehydrogenase 6idh: <FB mutations in amls are
associated Gith global dna hypermethylation ; <EM =, arguing the potential regulatory role of idh in
dna methylation machinery%
Qo far strong correlation betGeen epigenetic aberrations and cancers has been established
; <ES f <<E =% 'n the one hand, increased levels of dnmt< and dnmtJaFJb have been observed in
human malignancies 6eg lung cancer ; C< =, leuAemia ; <<< =, breast cancer ; <<B =:, indicative of
dnmt overe4pression in driving tumorigenesis% 'n the other hand, tumors often e4hibit global dna
hypomethylation, in conjunction Gith regional hypermethylation at cpg islands ; <<J =%
Uypermethylation of cpg islands on the promoter region silences gene e4pression ; <<K = and
usually occurs at the early stage of tumorigenesis, indicative of early cancer detection, especially in
patients Gith inherited genetic jeopardy ; <<L , <<V =% Almost LED of the genes have been shoGn to
go through methylation5mediated silencing in various cancer ; <<M =% ,he type of genes regulated by
cpg hypermethylation include tsgs, cell cycle related genes, dna mismatch repair genes, hormone
receptors and tissue or cell adhesion molecules% As an e4ample, the tsgs, liAe fhit ; <<S =, GGo4
; <<S , <<C = and rassf<a ; <BE = in lung cancer ; C< , <<< =, p<L and estrogen receptor ; <B< = in
leuAemia, are hypermethylated% ,sg suppression offers proliferative benefits to tumor cells% It is also
clear that dna methylation plays an important role in the generation of mutations in human tumors,
Ghich is evident by the observation that the high occurrence of c5to5t transitions found in pLJ tsg is
attributed to the spontaneous deamination of L5methylcytosine residues% Qince epigenetic
modifications could marA individuali$ed environmental effects and mediate genetic alterations
; <BB =, epigenetic consideration Gould significantly advance personali$ed cancer therapy%
0.1.".". eregulated epigenetics in non-cancer diseases
&pigenetic modifications regulate phenotypic variations in both health and disease, providing an
important GindoG to understand hoG environment5genome crosstalA controls health and initiates
diseases% &nvironmental factors 6intrinsic and outside stimuli: dynamically change dna and histones
leading to neG phenotypes as a result of the altered gene and mir e4pression ; <BJ =% In turn, the
dynamic epigenetics ensure a correct response of individual to a fre+uently changing environment
; <BJ =% bhen this dynamic balance is lost, illness occurs% Quch epigenetic5driven disease Gill cause
further alteration of other genetic and epigenetic signaling, resulting in numerous human disorders,
including autoimmunity5related diseases, heart failure ; <BK =, rheumatoid arthritis and systemic
lupus erythematosus ; <BL =, diabetes ; <BV =, mental disorders such as schi$ophrenia ; <BM =,
osteoarthritis 6oa: ; <BS = and others ; K< =% Qimilar to cancer, the molecular mechanisms under these
epigenetic5driven dcommone diseases are the abnormal e4pression of disease5specific genes or mirs
; <BS , <BC = resulting from aberrant dna methylation and histone modifications% ,hese deregulated
genes or mirs impact not only the disease development, but also the response to chemotherapy% .or
e4ample, through regulating the e4pression of drug metabolism and transport genes 6eg pKLE:, dna
methylation status creates inter5individual variation in drug responsiveness ; <JE =% ,herefore,
successful overcome of these diseases relies on the discovery of epigenetic biomarAers and the
application of appropriate inhibitory compounds in a disease and patient5dependent manner%
0.2. Epigenetic #iomar$ers in individualized cancer therap9
P-nceres normalmente apresentar hipometilao do dna global, hypermethylation cpg espec!fico e
modificaes de histonas aberrantes globais% &mbora As doenas humanas so impulsionadas pela
interfer*ncia din-mica entre a metilao do dna e modificaes de histonas de n(cleo, actualmente
o desenvolvimento de biomarcadores epigen0tica se concentra principalmente na metilao do adn
6revisto em ; SE =:, por causa do papel bem definido na patog0nese do cancro e da facilidade para
ser +uantificada por meio de t0cnicas correntes% Netilao 1o dna 0 a conse+>*ncia or+uestrada de
muitos atributos individuais e um importante mediador biol)gico dos efeitos ambientais de doenas
humanas ; <J< =%,0cnicas Nuito sens!veis t*m sido desenvolvidas para a medio de metilao do
adn ; <JB , <JJ =, incluindo a rcp ou +uantificaes O base de hplc% &mbora Qeja din-mica ao longo
do tempo, alguns cientistas apoiam o conceito de herana padro de metilao do dna e acreditar
sua variao entre os indiv!duos ; <JK =% Independentemente 1isso, por um lado, as regies 6por
e4emplo vmrs ; K< =: +ue no so alterados ao longo do tempo pode ser utili$ada como uma
assinatura epigen0tica por um indiv!duo, semelhante ao gen)tipo, e podem ser considerados como
candidatos para a avaliao de doena associada a metilao ; K< = e desenvolver epigenomics
personali$ados em medicina% @or 'utro lado, as regies +ue no mudam durante a fase de
patog*nese do c-ncer poderiam ser os biomarcadores certas para o tipo de tumor espec!fico em uma
determinada pessoa% Al0m 1isso, as terapias radiom0trico e +uimiota4ia, para um dado paciente,
so muito importantes moduladores epigen0tica e ir resultar na e4presso alterada do gene,
mutaes gen0ticas, modificaes de prote!nas, a instabilidade do cromossoma, e visivelmente
relacionada a terapia de leucemia5; <JL 5 <JM =% @ara &ste fim, pharmacoepigenomics, apesar de um
novo campo, est surgindo a promessa para a medicina personali$ada, no s) no c-ncer ; <JS =, mas
tamb0m outras doenas comuns 6diabetes mellitus tipo B ; <JC =, psicoses ; MV =:% ` 1efinida como a
Imanipulao epigenRmico do genoma para permitir o desenvolvimento de medicamentos mais
efica$es sob medida para o genoma de um indiv!duoI ; <KE =% @harmacoepigenomics Abrange todas
as reas da medicina cl!nica ; <KE = e est criando uma plataforma para abordar as variaes inter5
individuais na resposta O droga, dissecar e4presso g*nica assinatura indu$ida por drogas, prever os
efeitos colaterais da droga em ensaios pr05cl!nicos e descobrir novos medicamentos 6; <BV = e
revisto em ; <VC =:%
Uypermethylation regional cpg tem sido utili$ada como ferramenta para diagnosticar o c-ncer em
pacientes em uso de fluidos biol)gicos e bi)psias de tecidos ; <K< , <KB =% Uypermethylation
&spec!fico c-ncer pode ser evidenciado no soro de paciente com c-ncer ; <KJ =, e esses marcadores
t*m sido clinicamente utili$ada em diferentes tipos de tumores malignos humanos ; <KK 5 <KV =% @or
&4emplo, o melhor marcador de metilao do dna para deteco de cancro e a uma maior
probabilidade de sucesso como um biomarcador epigen0tica 0 a hipermetilao do gene da
glutationa s5transferase (gstp1) no cancro da pr)stata, o +ual foi utili$ado para ajudar a distinguir
entre o cancro da pr)stata e leses benignas ; <<V , <KM =% A 1eteco de gstp1 hypermethylation na
urina ; <KS = e soro ; <KC = apoiam fortemente a aplicao cl!nica% /o &ntanto, tanto hipo e hiper5
metilao t*m sido observadas em vrios loci e estgios em doenas cancerosas% &stas 'bservaes
defendem as dificuldades e comple4idades de descobrir se essas mudanas epigen0ticas so foras
para patog*nese ou a conse+>*ncia da fisiologia alterada em c0lulas de c-ncer de conduo% Assim,
a aplicao de biomarcadores epigen0ticos em c-nceres de cura 6por e4emplo, cancro colorectal:
tem +ue ser cauteloso devido aos resultados inconsistentes e inconclusivas de ensaios baseados em
metilao ; <JS =% &m Algumas circunst-ncias, hipometilao e hipometilantes agentes podem
promover a tumorig*nese ; <BV =, devido aos oncogenes reativados, apoiando a necessidade urgente
de all5inclusive biomarcadores epigen0ticos com igualmente contar com os dois etg e oncogenes%
0.". 7erapia (lvo-hipermetilao
As regies do promotor de cerca de LED dos genes humanos cont*m um ou mais ilhas cpg ; <LE =,
uma ve$ metilados, ocorre o silenciamento do gene% Pada ,ipo de tumor tem um perfil (nico de
ilhas cpg hipermetilado ; <L< , <LB =% 1ada A nature$a revers!vel de modificaes epigen0ticas
; <LJ =, as atividades dnmt aberrantes so os alvos mais atraentes, tanto para o desenvolvimento de
biomarcadores e gerao de drogas anti5c-ncer% ,he Aim of targeting dnmt activities or depigenetic
therapye is to reverse epigenetic silencing and reactive various tsgs in vitro and in vivo to induce a
therapeutic effect, liAe cell differentiation, groGth arrest or apoptosis ; <LK =% A$acitidine 6vida$a:
and decitabine 6dacogen:, the dnmt inhibitors, Gere the first successfully developed and fda5
approved epigenetic drugs in myelodysplastic syndromes 6mds: and being investigated in aml
; <LL f <LM =% ,hese Gere folloGed by fda5approved hdac inhibitors, vorinostat 6$olin$a: and
romidepsin 6istoda4:% ,here are other depigenetic drugse currently being used in clinical trials or
under various stages of preclinical development% ,o date, epigenetic therapy has achieved
impressive therapeutic efficacy and numerous patients have complete remission, particularly in
leuAemias ; <LS =%
UoGever, epigenetic5targeted therapies face many challenges, including inefficient drug delivery,
lacA of predictive biomarAers, une4plained mechanisms of sensitivity and resistance, and feG
responses in solid cancers ; <LC f <V< =% Wecause there are no suitable biomarAers available to
detect cancer cell metastasis and invasion, over VED of cancer patients have hidden or over
metastatic colonies Ghen they shoG up at the clinics% At this stage the tumors display the highest
heterogeneity, thereby no suitable therapeutic regimes are available% .urther, the common
chemotherapy, liAe decitabine, suffers many pitfalls, such as loG stability in current delivery vehicle
; <VB =, cell cycle5dependent activity ; <VJ =, loG efficiency of dna incorporation ; <VK =, lacA of
obvious inhibitory effect on dnmtJa and dnmtJb ; <VK , <VL =, and the development of drug
resistance ; <VV , <VM =% Among those, i believe that drug delivery efficiency is the most critical
barrier to effectively translate the leuAemia accomplishment to solid cancer ; <V< =%
"o to#
2. Conclusion and 'uture perspective
,he main emphasis of this article is rendered to the interface or the coordination of personali$ed5
and nano5 medicine taAing into account epigenetics in cancer management% Quch selection is
originated from the uni+ue feature and re+uirement of personali$ed health care, the only strategy
that can be used to cure cancer% ,oday, individuali$ed medicine, nanomedicine and epigenetic
targeted therapy, mainly from independent practice point of vieG, have been broadly employed in
clinics% bhile remarAably therapeutic efficacy has been accomplished, overall survival of cancer
patients has changed little% Pertainly multiple factors contribute to such discouraging outcomes, but
the chemotherapeutic failure could be mainly as result of the influences of done5si$e5fits5alle
standard protocol% As such, the ideal therapeutics relies on the ma4imal consolidation of
personali$ed therapy into nanomedicine and epigenetics, applying the right drug and dose Gith
appropriate delivery vehicles conjugated Gith specific biomarAer to a given patient at the right time
6refer to the diagram figure a:%
&pigenetic aberrations and genetic alterations cooperatively and dynamically drive almost all
human illnesses, thereby representing attractive targets for therapeutic interventions% ,he
identifications and employment of genetic and epigenetic biomarAers have revolutioni$ed disease
management% Among them, Ainase5targeted therapies represent several cases of successful
personali$ed medicine, because these approaches emphasi$e patient]s personal attributes at the
molecular or chromosomal level% UoGever, the information used here represents only tiny part of
patient]s molecular signatures, and most clinical and biological characteri$ation still remains
une4plored% ,his can e4plain Ghy such targeted therapy eventually failed, Ghile successful initially%
,o overcome the aforementioned therapeutic pitfalls, comprehensive characteri$ation of the disease
biology for specific patient 6responder versus non5responder or complete remission versus relapse:
is a must, Ghich shall be assisted through systemic approach using domicse technologies% ,he
domicse results are useful for early detection of disease, predicting patient response to therapy and
developing biomarAers to enable effective targeting of drug delivery modalities to the disease site%
Among the domicse technologies, genomics have achieved the most detailed and comprehensive
studies, but most gene e4pression signatures from cell lines and patient samples, Ghich reflect only
small time GindoG of disease development, are lacAing therapeutic meaning thereby not into clinic
yet ; <VS =% @roteomic profiling has huge potential to yield more direct ansGers to functional and
pharmacologic +uestions than transcriptional profiling ; <K< =, because physiological functions are
e4ecuted by proteins% UoGever, the inconsistence of protein modifications dynamically limits the
application of proteomics marAer to individuali$ed medicine%
'f all domicse information, epigenomics Gould be the most essential leader in developing
personali$ed5 and nano5 medicine, as epigenetics is the record of personal internal and e4ternal
stimuli 6eg maternal, nutrition and living:, not only determining other omics 6eg transcriptomics and
metabolomics:, but also inducing gene mutations thereby affecting the genomics% .urthermore, all
chemotherapies themselves are one of the most important drivers to epigenetic changes% Actually
there e4ists a feedbacA loop betGeen epigenetics and chemotherapies, in Ghich aberrant epigenetic
biomarAers implicate and determine the selection of chemotherapies, Ghereas the chemo5treatment
non5specifically modulates epigenetic codes thereby generating neG epigenetic aberrations,
eventually even chemotherapy5induced cancer 6eg leuAemia:% 1ifferent patients Gould have distinct
response to even the same drug delivered by similar vehicles thereby generating patient5specific
drug5induced epigenetic biomarAers% ,hus epigenetic changes fully represent personali$ed traits and
e4plain Ghy cooperation of epigenetics Gould enhance personali$ed nanomedicine%
,he last point to be considered for the development of epigenetic5mediated personali$ed
nanomedicine is the dynamics of cancer pathogenesis as Gell as pre5 and post5drug treatment% ,he
communication and interaction among tumor cells, stromal cells and host immune system are
undergoing changes all the time% As such, the biomarAers for cancer diagnostics and therapeutics,
the choice of drugs, delivery vehicles and the vehicle5conjugated tumor specific ligands should be
changed judiciously, not only from patient to patient, tumor to tumor, but also from cell to cell and
pre5 to post5 drug treatment% /ovel nanotechnologies Gill be indispensable to discover these
dynamic epigenetic biomarAers, specifically the sparse biomarAers hidden in barely available
materials% Although being largely confined to cancer in this article, epigenetics5driven personali$ed
nanomedicine Gill become greatly attractive options for clinicians GorAing on other common
diseases 6eg heart failure, osteoarthritis:% 'verall, Ge are increasingly hopeful that AnoGledge about
a patient]s proteomic, genetic, epigenetic and metabolic figures could be integrated to tailor medical
care to that individual]s needs% It is also hopeful that the alliance of personali$ed nanomedicine Gith
epigenetics Gould bring to us the unsurpassed health care%
"o to#
(gradecimentos
,his GorA Gas supported partially by nih grants rE<ca<KCVBJ 6s% Liu:, rB<ca<LLC<L 6s% Liu: and
hormel foundation 6s% Liu:% ,he author specifically thanAs drs% Lai5chu Gu and sudha agarGal at the
ohio state university for their much appreciated assistance in proofreading and editing this
manuscript and picture% ,he author is grateful to drs% 2obert j% Lee and l% iames lee at the ohio state
university and dr% bei ding at mayo clinic for their valuable thoughts, criticisms and insights%
"o to#
(5reviaturas
Lmc
L5methylcytosine
Lhmc
L5hydro4ymethylcytosine
Abc
Adenosine La5triphosphate5binding cassette
Aml
Acute myeloid leuAemia
Atp
Adenosine La5triphosphate
Wcr
WreaApoint cluster region
Wrca<
Wreast cancer type <
PbfY
Pore binding factor Y
Pbp
@rote!na de ligao de creb
Pml
Phronic myelogenous leuAemia
Preb
Pamp response element5binding
1nmt
1na metiltransferase
1o4
1o4orubicin
&gfr
&pidermal groGth factor receptor
&r
&strogen receptor
&rbbB
35erb5bB erythroblastic leuAemia viral oncogene homolog B
&to
&ight5tGenty5one
.hit
.ragile histidine triad
.ltJ
.ms5liAe tyrosine Ainase receptor5J
"stp<
"lutathione s5transferase gene
Uat
Uistone acetylase
Udac
Uistone deacetylase
Udmt
Uistone demethyltransferase
UerB
Uuman epidermal groGth factor receptor B
Ugp
@rojeto genoma humano
Umt
Uistone methyltransferase
Idh
Isocitrate dehydrogenase
Il5J
InterleuAin J
Nds
Nyelodysplastic syndrome
Nirs
Nicrornas
No$
Nonocytic leuAemia $inc finger
Nri
2esson-ncia magn0tica
N$
Nono$ygotic
@iJA
@hosphatidylinositol J5Ainase
@$lf
@romyelocytic leuAemia $inc5finger protein
2ar5g
2etinoic acid receptor alpha
2assf<a
2as5association domain family <a gene
Qam
Q5adenosyl5methionine
Qmmhc
Qmooth muscle myosin heavy chain
Qnps
Qingle5nucleotide polymorphisms
,et
,en5eleven5translocation
,sgs
,umor suppressor genes
Ttrs
Tntranslated regions
3mrs
Inter5individual variability
bGo4
bG5domain containing o4idoreductase
"o to#
6otas de rodap
Con'lito de interesses
,he author states no conflict of interest%
8en-ncia do editor: este 0 um ar+uivo pdf de um manuscrito in0dito, +ue foi aceito para
publicao% Pomo Tm servio aos nossos clientes estamos oferecendo essa verso inicial do
manuscrito% ' Nanuscrito ser submetido a edio de te4to, diagramao e reviso da prova,
resultando antes de ser publicado em sua forma citvel final% @or .avor, note +ue durante os erros de
processo de produo pode ser descoberto o +ue poderia afetar o conte(do, e todos os avisos legais
+ue se aplicam para a revista pertencem%
"o to#
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K<% .einberg Ap, iri$arry ra, fradin d, aryee mj, muraAami p, aspelund t, eiriAsdottir g, harris tb,
launer l, gudnason v, fallin md% @ersonali$ed epigenomic signatures that are stable over time and
covary Gith body mass inde4% Qcience ,ranslational medicine% BE<EX B #KCraVM% ; pmc free article =
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KB% Andersen in, sathyanarayanan s, di bacco a, chi a, $hang t, chen ah, dolinsAi b, Araus m, roberts
b, arthur G, Alinghoffer ra, gargano d, li l, feldman i, lynch b, rush j, hendricAson rc, blume5jensen
p, paGelet$ cp% @athGay5based identification of biomarAers for targeted therapeutics# personali$ed
oncology Gith piJA pathGay inhibitors% Qcience ,ranslational medicine% BE<EX B #KJraLL%; @ubNed =
KJ% Leary 2j, Ainde i, diehl f, schmidt A, clouser c, duncan c, antipova a, lee c, mcAernan A, de la
vega fm, Ain$ler AG, vogelstein b, dia$ la, jr, velculescu ve% 1evelopment of personali$ed tumor
biomarAers using massively parallel se+uencing% Qcience ,ranslational medicine% BE<EX B #BEra<K%
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song y, chirieac lr, Aaur r, lightboGn a, simendinger j, li t, padera rf, garcia5echeverria c, Geissleder
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g<Bd and piAJca h<EKMr murine lung cancers% /ature Nedicine% BEESX <K #<JL<f<JLV%; @NP .ree
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KL% iimeno A, messersmith Ga, hirsch fr, franAlin Ga, ecAhardt sg% ^ras mutations and sensitivity to
epidermal groGth factor receptor inhibitors in colorectal cancer# practical application of patient
selection% iournal 'f clinical oncology # official journal of the american society of clinical
oncology%BEECX BM #<<JEf<<JV% ; pubmed =
KV% Nardis &r% ,he l<,EEE genome, the l<EE,EEE analysish "enome Nedicine% BE<EX B #SK%; @NP
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KM% Uahn bc, Geinberg ra% Nodelling the molecular circuitry of cancer% /ature 2evieGs
cancer% BEEBX B#JJ<fJK<% ; pubmed =
KS% Liotta L, petricoin e% Nolecular profiling of human cancer% /ature 2evieGs
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KC% @etricoin &f, $oon Ac, Aohn ec, barrett jc, liotta la% Plinical proteomics# translating benchside
promise into bedside reality% /ature 2evieGs drug discovery% BEEBX < #VSJfVCL% ; pubmed =
LE% iain ^A% Advances in the field of nanooncology% WNP Ned% BE<EX S #SJ% ; pmc free article =
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L<% Noghimi Qm, hunter ac, murray jc% /anomedicine# current status and future prospects% ,he
.aseb journal # official publication of the federation of american societies for e4perimental
biology% BEELX <C#J<<fJJE% ; pubmed =
LB% Qchroeder A, heller da, GinsloG mm, dahlman je, pratt gG, langer r, jacAs t, anderson dg%
,reating metastatic cancer Gith nanotechnology% /ature 2evieGs cancer% BE<BX <B #JCf
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LJ% WouAany @e, morss a, liao Gc, henslee b, jung h, $hang 4, yu b, Gang 4, Gu y, li l, gao A, hu 4,
$hao 4, hemminger o, lu G, lafyatis gp, lee lj% /anochannel electroporation delivers precise amounts
of biomolecules into living cells% /ature /anotechnology% BE<<X V #MKMfMLK% ; pubmed =
LK% @eer 1, Aarp jm, hong s, faroAh$ad oc, margalit r, langer r% /anocarriers as an emerging
platform for cancer therapy% /ature /anotechnology% BEEMX B #ML<fMVE% ; pubmed =
LL% Arvi$o 2r, rana s, miranda or, bhattacharya r, rotello vm, muAherjee p% Nechanism of anti5
angiogenic property of gold nanoparticles# role of nanoparticle si$e and surface
charge% /anomedicine # nanotechnology, biology, and medicine% BE<<X M #LSEfLSM% ; pmc free
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LV% Arvi$o 2r, miranda or, thompson ma, pabelicA cm, bhattacharya r, robertson jd, rotello vm,
praAash ys, muAherjee p% &ffect of nanoparticle surface charge at the plasma membrane and
beyond%/ano Letters% BE<EX <E #BLKJfBLKS% ; pmc free article = ; pubmed =
LM% "aster 2s, hall da, nielsen ch, osterfeld sj, yu h, mach Ae, Gilson rj, murmann b, liao jc, gambhir
ss, Gang s4% Natri45insensitive protein assays push the limits of biosensors in medicine% /ature
Nedicine% BEECX <L #<JBMf<JJB% ; pubmed =
LS galan$ha ei, shashAov ev, Aelly t, Aim jG, yang l, $harov vp% In 3ivo magnetic enrichment and
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LC% Qanhai br, saAamoto jh, canady r, ferrari m% Qeven challenges for nanomedicine% /ature
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VE% 1avis Ne, $ucAerman je, choi ch, seligson d, tolcher a, alabi ca, yen y, heidel jd, ribas a%
&vidence of rnai in humans from systemically administered sirna via targeted
nanoparticles% /ature%BE<EX KVK #<EVMf<EME% ; pmc free article = ; pubmed =
V<% Qhvedova Aa, castranova v, Aisin er, schGegler5berry d, murray ar, gandelsman v$, maynard a,
baron p% &4posure to carbon nanotube material# assessment of nanotube cytoto4icity using human
Aeratinocyte cells% iournal 'f to4icology and environmental health part a% BEEJX VV #<CECf<CBV%
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VB% Lam PG, james jt, mcclusAey r, hunter rl% @ulmonary to4icity of single5Gall carbon nanotubes in
mice M and CE days after intratracheal instillation% ,o4icological Qciences # an official journal of the
society of to4icology% BEEKX MM #<BVf<JK% ; pubmed =
VJ% ^ipen Um, lasAin dl% Qmaller is not alGays better# nanotechnology yields
nanoto4icology% American iournal of physiology lung cellular and molecular
physiology% BEELX BSC #lVCVfVCM% ; pubmed =
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pharmacology% BEELX<KV #SSBfSCJ% ; pmc free article = ; pubmed =
VL% Phen m, meng h, 4ing g, chen c, $hao y, jia g, Gang t, yuan h, ye c, $hao f, chai $, $hu c, fang 4,
ma b, Gan l% Acute to4icological effects of copper nanoparticles in vivo% ,o4icology
Letters%BEEVX <VJ #<ECf<BE% ; pubmed =
VV% Uussain Qm, javorina aA, schrand am, duhart hm, ali sf, schlager jj% ,he interaction of
manganese nanoparticles Gith pc5<B cells induces dopamine depletion% ,o4icological Qciences # an
official journal of the society of to4icology% BEEVX CB #KLVfKVJ% ; pubmed =
VM% iain ^A% Applications of nanobiotechnology in clinical diagnostics% Plinical
Phemistry% BEEMX LJ#BEEBfBEEC% ; pubmed =
VS% 1ebbage @% ,argeted drugs and nanomedicine# present and future% Purrent @harmaceutical
design%BEECX <L #<LJf<MB% ; pubmed =
VC% &merich 1f, thanos cg% ,he pinpoint promise of nanoparticle5based drug delivery and molecular
diagnosis% Wiomolecular &ngineering% BEEVX BJ #<M<f<SK% ; pubmed =
ME% Paruthers Qd, Ginter pm, GicAline sa, lan$a gm% ,argeted magnetic resonance imaging contrast
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journal of the society of magnetic resonance in medicine F society of magnetic resonance in
medicine% BEELX LJ #VB<fVBM% ; pubmed =
MB% Wlume5jensen p, hunter t% 'ncogenic Ainase signalling% /ature% BEE<X K<< #JLLfJVL% ; pubmed =
MJ% 3ogelstein W, Ain$ler AG% Pancer genes and the pathGays they control% /ature
Nedicine% BEEKX <E#MSCfMCC% ; pubmed =
MK% &ngelman ia, luo j, cantley lc% ,he evolution of phosphatidylinositol J5Ainases as regulators of
groGth and metabolism% /ature 2evieGs genetics% BEEVX M #VEVfV<C% ; pubmed =
ML% Uuang i, manning bd% A comple4 interplay betGeen aAt, tscB and the tGo mtor
comple4es%Wiochemical Qociety transactions% BEECX JM #B<MfBBB% ; pmc free article = ; pubmed =
MV% AbdolmaleAy Um, $hou jr, thiagalingam s, smith cl% &pigenetic and pharmacoepigenomic
studies of major psychoses and potentials for therapeutics% @harmacogenomics% BEESX C #<SECf
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MM% AnGay Nd, cupp as, u$umcu m, sAinner mA% &pigenetic transgenerational actions of endocrine
disruptors and male fertility% Qcience% BEELX JES #<KVVf<KVC% ; pubmed =
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epigenetic differences associated Gith prenatal e4posure to famine in humans% @roceedings 'f the
national academy of sciences of the united states of america% BEESX <EL #<MEKVf<MEKC%; @NP .ree
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MC% Nc"oGan @o, sasaAi a, d]alessio ac, dymov s, labonte b, s$yf m, turecAi g, meaney mj%
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abuse%/ature /euroscience% BEECX <B #JKBfJKS% ; pmc free article = ; pubmed =
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agouti gene e4pression in avyFa mice% ,he .aseb journal # official publication of the federation of
american societies for e4perimental biology% <CCSX <B #CKCfCLM% ; pubmed =
SB% beaver Ic, cervoni n, champagne fa, d]alessio ac, sharma s, secAl jr, dymov s, s$yf m, meaney
mj% &pigenetic programming by maternal behavior% /ature /euroscience% BEEKX M #SKMfSLK%
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SJ% WoAs Np, derAs em, Geisenberger dj, strengman e, janson e, sommer ie, Aahn rs, ophoff ra% ,he
relationship of dna methylation Gith age, gender and genotype in tGins and healthy controls% @loQ
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SK% Phristensen Wc, houseman ea, marsit cj, $heng s, Grensch mr, Giemels jl, nelson hh, Aaragas mr,
padbury jf, bueno r, sugarbaAer dj, yeh rf, GiencAe jA, Aelsey At% Aging and environmental
e4posures alter tissue5specific dna methylation dependent upon cpg island conte4t% @LoQ
"enetics% BEECXL #e<EEEVEB% ; pmc free article = ; pubmed =
SL schreiber sl, bernstein be% Qinali$ao Nodelo de rede de cromatina celular BEEBX <<<%#%% MM<5
MMS; pubmed =
SV% ,urner Wm% 1efining an epigenetic code% /ature Pell biology% BEEMX C #BfV% ; pubmed =
SM% Wjornsson Ut, sigurdsson mi, fallin md, iri$arry ra, aspelund t, cui h, yu G, rongione ma,
eAstrom tj, harris tb, launer lj, eiriAsdottir g, leppert mf, sapien$a c, gudnason v, feinberg ap% Intra5
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american medical association% BEESX BCC #BSMMfBSSJ% ; pmc free article = ; pubmed =
SS% Li W, carey m, GorAman jl% ,he role of chromatin during transcription% Pell% BEEMX <BS #MEMf
M<C%; @ubNed =
SC% Werger Ql, Aou$arides t, shieAhattar r, shilatifard a% An operational definition of
epigenetics% "enes j development% BEECX BJ #MS<fMSJ% ; pmc free article = ; pubmed =
CE% "ar$on 2, liu s, fabbri m, liu $, heaphy ce, callegari e, schGind s, pang j, yu j, muthusamy n,
havelange v, volinia s, blum G, rush lj, perrotti d, andreeff m, bloomfield cd, byrd jc, chan A, Gu lc,
croce cm, marcucci g% Nicrorna5BCb induces global dna hypomethylation and tumor suppressor
gene ree4pression in acute myeloid leuAemia by targeting directly dnmtJa and Jb and indirectly
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C<% .abbri N, gar$on r, cimmino a, liu $, $anesi n, callegari e, liu s, alder h, costinean s, fernande$5
cymering c, volinia s, guler g, morrison cd, chan AA, marcucci g, calin ga, huebner A, croce cm%
Nicrorna5BC family reverts aberrant methylation in lung cancer by targeting dna methyltransferases
Ja and Jb% @roceedings 'f the national academy of sciences of the united states of
america% BEEMX <EK #<LSELf<LS<E% ; pmc free article = ; pubmed =
CB% ^ou$arides ,% Phromatin modifications and their function% Pell% BEEMX <BS #VCJf
MEL% ; pubmed =
CJ% Allis Pd, berger sl, cote j, dent s, jenuGien t, Aou$arides t, pillus l, reinberg d, shi y, shieAhattar
r, shilatifard a, GorAman j, $hang y% /eG nomenclature for chromatin5modifying
en$ymes%Pell% BEEMX <J< #VJJfVJV% ; pubmed =
CK% Nohn ., schubeler d% "enetics and epigenetics# stability and plasticity during cellular
differentiation%,rends In genetics # tig% BEECX BL #<BCf<JV% ; pubmed =
CL% bitt ', deub$er he, milde t, oehme i% Udac family# Ghat are the cancer relevant targetsh Pancer
Letters% BEECX BMM #SfB<% ; pubmed =
CV% 1oAmanovic N, clarAe c, marAs pa% Uistone deacetylase inhibitors# overvieG and
perspectives%Nolecular Pancer research # mcr% BEEMX L #CS<fCSC% ; pubmed =
CM% beichert b% Udac e4pression and clinical prognosis in human malignancies% Pancer
Letters% BEECXBSE #<VSf<MV% ; pubmed =
CS% Liu ^, Gang yf, cantemir c, muller mt% &ndogenous assays of dna methyltransferases# evidence
for differential activities of dnmt<, dnmtB, and dnmtJ in mammalian cells in vivo% Nolecular And
cellular biology% BEEJX BJ #BMECfBM<C% ; pmc free article = ; pubmed =
CC% Uerman ig, baylin sb% "ene silencing in cancer in association Gith promoter
hypermethylation% / &ngl j med% BEEJX JKC #BEKBfBELK% ; pubmed =
<EE% ,ing Ah, jair AG, su$uAi h, yen rG, baylin sb, schuebel Ae% Ppg island hypermethylation is
maintained in human colorectal cancer cells after rnai5mediated depletion of dnmt<% /at
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<E<% 2hee I, bachman Ae, parA bh, jair AG, yen rG, schuebel Ae, cui h, feinberg ap, lengauer c,
Ain$ler AG, baylin sb, vogelstein b% 1nmt< and dnmtJb cooperate to silence genes in human cancer
cells% /ature% BEEBX K<V #LLBfLLV% ; pubmed =
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ishiAaGa f, li e, ueda hr, naAayama j, oAano m% Naintenance of self5reneGal ability of mouse
embryonic stem cells in the absence of dna methyltransferases dnmt<, dnmtJa and dnmtJb% "enes
,o cells # devoted to molecular j cellular mechanisms% BEEVX << #SELfS<K% ; pubmed =
<EJ% 2obert Nf, morin s, beaulieu n, gauthier f, chute ic, barsalou a, macleod ar% 1nmt< is re+uired
to maintain cpg methylation and aberrant gene silencing in human cancer cells% /ature
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<EK% billiams ^, christensen j, pedersen mt, johansen jv, cloos pa, rappsilber j, helin A% ,et< and
hydro4ymethylcytosine in transcription and dna methylation fidelity% /ature% BE<<X KMJ #JKJfJKS%
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<EL% Ito Q, shen l, dai +, Gu sc, collins lb, sGenberg ja, he c, $hang y% ,et proteins can convert L5
methylcytosine to L5formylcytosine and L5carbo4ylcytosine% Qcience% BE<<X JJJ #<JEEf<JEJ%; @NP
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<EV% ,ahiliani N, Aoh Ap, shen y, pastor Ga, banduAGala h, brudno y, agarGal s, iyer lm, liu dr,
aravind l, rao a% Ponversion of L5methylcytosine to L5hydro4ymethylcytosine in mammalian dna by
mll partner tet<% Qcience% BEECX JBK #CJEfCJL% ; pmc free article = ; pubmed =
<EM% .igueroa Ne, abdel5Gahab o, lu c, Gard ps, patel j, shih a, li y, bhagGat n, vasanthaAumar a,
fernande$ hf, tallman ms, sun $, GolniaA A, peeters jA, liu G, choe se, fantin vr, paietta e, loGenberg
b, licht jd, godley la, delGel r, valA pj, thompson cb, levine rl, melnicA a% LeuAemic idh< and idhB
mutations result in a hypermethylation phenotype, disrupt tetB function, and impair hematopoietic
differentiation% Pancer Pell% BE<EX <S #LLJfLVM% ; pmc free article = ; pubmed =
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therapy5related leuAemia secondary to breast cancer% LeuAemia # official journal of the leuAemia
society of america, leuAemia research fund, uA% BEEEX <K #<E<Kf<E<M% ; pubmed =
<JM% 3alentini Pg, fianchi l, voso mt, caira m, leone g, pagano l% Incidence of acute myeloid
leuAemia after breast cancer% Nediterranean iournal of hematology and infectious
diseases% BE<<X J#eBE<<EVC% ; pmc free article = ; pubmed =
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@harmacoepigenomics in colorectal cancer# a step forGard in predicting prognosis and treatment
response%@harmacogenomics% BEESX C #<CEJf<C<V% ; pubmed =
<JC% Nanolopoulos 3g, ragia g, tavridou a% @harmacogenomics of oral antidiabetic medications#
current data and pharmacoepigenomic perspective% @harmacogenomics% BE<<X <B #<<V<f
<<C<% ; pubmed =
<KE% Lujambio A, loGe sG% ,he microcosmos of cancer% /ature% BE<BX KSB #JKMfJLL% ; pmc free
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<K<% Laird @G% ,he poGer and the promise of dna methylation marAers% /ature 2evieGs
cancer% BEEJX J#BLJfBVV% ; pubmed =
<KB% QhivapurAar /, ga$dar af% 1na methylation based biomarAers in non5invasive cancer
screening%Purrent Nolecular medicine% BE<EX <E #<BJf<JB% ; pmc free article = ; pubmed =
<KJ% &steller N, sanche$5cespedes m, rosell r, sidransAy d, baylin sb, herman jg% 1etection of
aberrant promoter hypermethylation of tumor suppressor genes in serum dna from non5small cell
lung cancer patients% Pancer 2esearch% <CCCX LC #VMfME% ; pubmed =
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of colon cancer5specific methylation of the none4pressed vimentin gene% iournal 'f the national
cancer institute% BEELX CM #<<BKf<<JB% ; pubmed =
<KL% Uo+ue No, begum s, topaloglu o, chatterjee a, rosenbaum e, van crieAinge G, Gestra Gh,
schoenberg m, $ahuraA m, goodman sn, sidransAy d% cuantitation of promoter methylation of
multiple genes in urine dna and bladder cancer detection% iournal 'f the national cancer
institute% BEEVX CS #CCVf<EEK% ; pubmed =
<KV% WelinsAy Qa, liechty Ac, gentry fd, Golf hj, rogers j, vu A, haney j, Aennedy tc, hirsch fr, miller
y, franAlin Ga, herman jg, baylin sb, bunn pa, byers t% @romoter hypermethylation of multiple genes
in sputum precedes lung cancer incidence in a high5risA cohort% Pancer 2esearch% BEEVX VV #JJJSf
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<KM% Lee bh, morton ra, epstein ji, brooAs jd, campbell pa, bova gs, hsieh Gs, isaacs Gb, nelson Gg%
Pytidine methylation of regulatory se+uences near the pi5class glutathione s5transferase gene
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the united states of america% <CCKX C< #<<MJJf<<MJM% ; pmc free article = ; pubmed =
<KS% Uo+ue No, topaloglu o, begum s, henri+ue r, rosenbaum e, van crieAinge G, Gestra Gh,
sidransAy d% cuantitative methylation5specific polymerase chain reaction gene patterns in urine
sediment distinguish prostate cancer patients from control subjects% iournal 'f clinical oncology #
official journal of the american society of clinical oncology% BEELX BJ #VLVCfVLML% ; pubmed =
<KC% 2ichiardi L, fiano v, vi$$ini l, de marco l, delsedime l, aAre o, tos ag, merletti f% @romoter
methylation in apc, run4J, and gstp< and mortality in prostate cancer patients% iournal 'f clinical
oncology # official journal of the american society of clinical oncology% BEECX BM #J<V<fJ<VS%
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<LE% IoshiAhes Ip, $hang m+% Large5scale human promoter mapping using cpg islands% /ature
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<L<% Postello if, fruhGald mc, smiraglia dj, rush lj, robertson gp, gao 4, Gright fa, feramisco jd,
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<LB% &steller N, corn pg, baylin sb, herman jg% A gene hypermethylation profile of human
cancer%Pancer 2esearch% BEE<X V< #JBBLfJBBC% ; pubmed =
<LJ% ^elly ,A, de carvalho dd, jones pa% &pigenetic modifications as therapeutic targets% /ature
Wiotechnology% BE<EX BS #<EVCf<EMS% ; pmc free article = ; pubmed =
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research%BE<EX <KL #<CfKE% ; pubmed =
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tumor suppressor role for p<LinAKb% Pancer 2es% <CCVX LV #MBBfMBM% ; pubmed =
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,he estrogen receptor cpg island is methylated in most hematopoietic neoplasms% Pancer
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<LM% Issa ip, Aantarjian hm, AirApatricA p% A$acitidine% /at 2ev drug discov% BEELX K #BMLfBMV%
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santhanam r, Gang h, curfman jp, devine sm, jacob s, garr c, Aefauver c, perrotti d, chan AA,
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<LC% NarAs @a% &pigenetic targeted anti5cancer drugs# an unfolding story% 'ncology 6Gilliston
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<VE% Woumber k, issa jp% &pigenetics in cancer# Ghat]s the futureh 'ncology 6Gilliston
parA: BE<<X BL#BBEfBBV% BBS% ; pubmed =
<V<% Issa ip, Aantarjian hm% ,argeting dna methylation% Plinical Pancer research # an official journal
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resistance to the deo4ycytidine analogues cytarabine 6arac: and L5a$a5Ba5deo4ycytidine 6dac: in a rat
model for acute myeloid leuAemia is mediated by mutations in the deo4ycytidine Ainase 6dcA:
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