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Dep.

Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera
Utara
24 November 2012, KBK SM-7, FK USU

The Biology of Cancer


Special characteristics of cancer cells.
1. Uncontrolled proliferation
2. Dedifferentiation and loss of
function.
3. Invasiveness
4. Metastasis

Modalities of
Chemotherapy
Curative
Total irradication of cancer cells; possible?
The concept of log kill
If 109 cells present, and drug kills 99.999%, then 0.001%
left------- still 10.000 cells left alive
This is a 5-log kill

Palliative
Alleviation of symptoms
Avoidance of life-threatening toxicity

Adjuvant follow surgery/radiation


Breast, ovarian, colon

Neoadjuvant prior to surgery


Osteosarcoma, rectal, head & neck

Prevention
Tamoxifen, ASA, folic acid, sunscreen, lead suits?

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera
Utara

The Classification of Anticancer


Drugs

According to chemical structure and


resource of the drug;
According to biochemistry mechanisms of
anticancer action;
According to the cycle or phase specificity
of the drug

The Classification of Anticancer


Drugs

According to chemical structure and


resource of the drug:
Alkylating Agents, Antimetabolite, Antibiotics,
Plant Extracts Hormones Others

The Classification of Anticancer


Drugs

According to the cycle or phase specificity of


the drug:
cell cycle nonspecific agents (CCNSA)
cell cycle specific agents (CCSA)

The Basic Concept of


Cell Generation Cycle
The cycle of cell replication includes:
M Mitosis phase
G1 Gap1, period before S phase
S DNA synthesis phase
G2 Gap2,period after S phase

Growth Fraction (GF

The Cell Cycle

Growth Fraction (GF)

GF

Proliferating cell group


Total tumor cell group

CCNSA drugs that are active throughout


the cell cycle.
CCSA: drugs that act during a specific
phase of the cell cycle.

Cell cycle specific agents and Cell cycle


Non-specific agents

Cell Cycle Nonspecific Agents (CCNSA)


drugs that are active throughout the cell cycle

Alkylating Agents
Platinum Compounds
Antibiotics

Cell cycle specific agents and Cell cycle


Non-specific agents

Cell Cycle Specific Agents (CCSA)


drugs that act during a specific phase of
the cell cycle
S Phase Specific Drug:
Antimetabolites, Topoisomerase Inhibitors
M Phase Specific Drug:
Vinca Alkaloids, Taxanes
G2 Phase Specific Drug:
Bleomycin

Mechanism of Anticancer Drugs


o Block nucleic acid (DNA, RNA) biosynthesis
o Directly destroy DNA and inhibit DNA reproduction
o Interfere transcription and block RNA synthesis
o Interfere protein synthesis and function
o Influence hormone homeostasis

Block Nucleic Acid (DNA, RNA)


Biosynthesis
Antimetabolites:
o Folic Acid Antagonist: inhibit dihydrofolate reductase
(methotrexate)
o Pyrimidine Antagonist: inhibit thymidylate synthetase
(fluorouracil) ; inhibit DNA polymerase (cytarabine)
o Purine Antagonist: inhibit interconversion of purine
nucleotide (mercaptopurine)
o Ribonucleoside Diphosphate Reductase Antagonist:
(hydroxyurea)

The Classification of Anticancer Drugs


o

According to chemical structure and resource of


the drug;

Alkylating Agents, Antimetabolite, Antibiotics,


- Plant Extracts Hormones Others

According to biochemistry mechanisms of anticancer


action;
- Block nucleic acid biosynthesis
- Direct influence the structure and function of DNA
- Interfere transcription and block RNA synthesis
- Interfere protein synthesis and function
- Influence hormone homeostasis
- Others

According to the cycle or phase specificity of the


drug

Principles of chemotherapy
Classification of cytotoxic agents
Alkylating
Agents

AntiMetabolites

Mitotic
Inhibitors

Antibiotics

Others

Busulfan

Cytosine

Etoposide

Bleomycin

L-asparaginase

Carmustine

Arabinoside

Teniposide

Dactinomycin

Hydroxyurea

Chlorambucil

Floxuridine

Vinblastine

Daunorubicin

Procarbazine

Cisplatin

Fluorouracil

Vincristine

Doxorubicin

Cyclophospha
mide

Mercaptopurine

Vindesine

Mitomycin-C

Ifosfamide

Methotreaxate

Taxoids

Mitoxantrone

Melphalan

Plicamycin

Principles
of chemotherapy
Aim of combination
therapy
INCREASED EFFICACY

ACTIVITY
Different mechanisms of action
Different mechanisms of resistance

SAFETY
Compatible side effects

Problems With Cancer


Chemotherapy
Drug Toxicity
Drug Resistance

Principles of chemotherapy
Side effects of chemotherapy
Alopecia
Mucositis

Nausea/vomiting
Diarrhea
Cystitis

Pulmonary fibrosis
Cardiotoxicity
Local reaction

Sterility

Renal failure

Myalgia

Myelosuppression

Neuropathy

Phlebitis

TOXICITY OF ANTICANCER DRUGS


o Normal cells with a high growth fraction (bone marrow,
gastrointestinal mucosa, ovaries, and hair follicles) are
highly susceptible to the cytotoxic actions of anticancer
drugs.
o Bone marrow suppression is common with both alkylating
agents and antimetabolites; it is often the dose-limiting
toxicity.
o Drug dosage is usually titrated to avoid excessive
neutropenia (granulocytes < 500/dl) or thrombocytopenia
(platelets < 20.000/dl).
o The use of colony-stimulating factors decreases the
infection rate and the need for antibiotics.

Anticancer drug-specific toxicities


Drug
Bleomycin

Specific Toxicities
Pulmonary fibrosis, fevers, skin
hardening and blisters, anaphylaxis.

Cisplatin

Nephrotoxicity, acoustic and


peripheral neurophathy

Cyclophosph Hemorrhagic cystitis-mesna is


amide
protective (traps acrolein); ifosfamide
is similar to cyclophosphamide.
Doxorubicin Cardiomyopathy (eg, delayed heart
and
failure)-dexrazoxane is protective
daunorubicin (decreases free radical formation);
liposomal forms are less cardiotoxic.

Methorexate Myelosuppression (useleucovorin


(MTX)
rescue) and mucositis; crystalluria;
toxicity is enhanced by drugs that
displace MTX from plasma proteins
(eg, salicylates, sulfonamides).
Vincristine

Peripheral neuropathy (autonomic,


motor, and sensory); vinblastine is
less neurotoxic; paclitaxel also
causes sensory neuropathy

Mesna ( mercaptoethanesulfonate)

= forms a complex with acrolein,the metabolite


of cyclophosphamide that causes bladder
toxicity
=Dexrazoxane;blocks the formation of free rad
that are responsible for the cardiotoxicity of
rubicin
= Folinic acid is used to reverse
MTX toxicity

Drug Resistance

De novo Resistance

Acquired Resistance
Multidrug Resistance (MDR)

De novo resistance:
De novo resistance can be de novo genetic
(i.e. the cells are initially inherently resistant),
or can arise because drugs are unable to
reach the target cells because of permeability
barriers such as the blood-brain barrier

Drug Resistance

Acquired Resistance:

Acquired drug resistance may result from


genomic mutations, such as the induction
or deletion of enzymes involved in drug
inactivation or drug activation,
respectively.

Drug Resistance
Multidrug Resistance (MDR):
P-glycoprotein transports many naturally occurring drugs
out of neoplastic cells, and its induction may lead to
multidrug resistance.
=Inhibited by verapamil,diltiazem,
amiodarone,quinidine,ketoconazole,eritromisin
As scientific understanding of the mechanisms of drug
resistance increases, new treatments may be developed
to counteract resistance.

Tabel. Resistance to anticancer drugs


Mechanisms of Resistance

Anticancer Drugs Affected

o Increased DNA repair

Alkylating agents

o Formation of trapping
agents
o Changes in target
enzymes or receptors

Alkylating agents

o Decreased activation of
prodrugs
o Formation of druginactivating enzymes.
o Decreased drug
accumulation via increase
in P-gp transporters.

6-mercaptopurine, 5fluorouracil.

Etoposide, gonadal
hormones, methotrexate,
vincristine, vinblastine.

Purine and pyrimidine


antimetabolites.
Alkylating agents,
dactinomycin, methotrexate.

COMBINATION THERAPY
o Reduces resistance to drugs
o Increased effectiveness
o Access to sanctuary sites e.g. lungs, CSF.
o Each hospital has its own regiments
o Combinations selected to avoid overlapping
toxicity but:
o Causes spectrum of adverse effects but
minimises risk of lethal effects.

PRODRUGS
1. Cyclophosphamide 4Hydroxyphosphamide
2. Procarbazne dacarbazine
3. Merkaptopurine 6-merkaptopurine
ribozophosphate
4. Tioquann
6-tioquann-ribzophosphate
5. Fluorouracil 5-fluoro-deoxy- uracil
monophosphate
6. Mitomycin (only at the hypoxic tissue of
tumors)
7. Doxorubicin idarubicin

CYTOTOXIC DRUGS
A. Alkylating Agents
1. Mechanisms of action : The alkylating
agents are CCNS drugs.
a. They interact covalently with DNA bases,
especially at the N-7 position of guanine.
b. Nucleic acid functions are disrupted due
to cross-linking, abnormal base pairing,
and DNA strand breakage.

ALKYLATING AGENTS
Cyclophosphamide, Ifosphamide, Chlorambucil, Nitrosoureas
Cell- cycle-nonspecific drugs
combine with DNA of both malignant and normal cells and
thus damage not only malignant cells but also dividing
normal cells (the bone marrow and the GIT)
mechanisms: the alkyl groupings (ethyleneimine ions and
positively charged carbonium ions) are highly reactive, so
that combine with susceptible groups in cells and in tissue
fluids (SH, PO4)
The alkylating action on DNA leads to abnormal base
pairing or intra and interstrand links with DNA molecule

cytotoxic, mutagenic and teratogenic effects may


result from interaction with DNA

M e c h a n is m o f in tr a m o le c u la r b r id g in g o f D N A b y a lk y la tin g a g e n ts .
D N A

A lk y la tin g
agent

i.e .
A

C
A
C
G
T

=
=
=
=

a d e n in e
c y to s in e
g u a n in e
th y m id in e

Cyclophosphamide
an inactive prodrug
can be given orally
is activated by the CYP450 in liver as well as in
tumors.
with time, the active metabolite and also acrolein
are formed. The latter compound is responsible for
bladder toxicity (chemical hemorrhagic cystitis).
a wide spectrum antitumor and immunosuppressive
activity used as a part of combination therapy
regimens to treat lymphoma, breast cancer, bladder
cancer, ovarian cancer and various children
malignancies

T o x i c i t i e s:
bone marrow depression, granulocytopenia,
x
thrombocytopenia.
urotoxicity appears with chronic therapy M e s n a (2-mercaptoethanesulfonate sodium)
protects the urinary tract against the irritant effects
by supplying sulfhydryl groups to form a stable
thioether with acrolein. Mesna is given by IV
injection or po

The nitrosoureas:
Carmustine and Lomustine are potent bone marrow
toxins. Hepatotoxicity and nephrotoxicity.
Broad spectrum of activity (solid tumors, in particular
brain tumors).

B. Antimetabolites
1. Mechanisms of action : Antimetabolites are CCS
drugs.
a. They are structurally similar to endogenous
compounds.
b. Anticancer and immunosuppressive actions result
from interference with the metabolic functions of
folic acid, purines, and pyrimidines.
2. Methotrexate (MTX) is an analog of folic acid that
inhibits dihydrofolate reductase and other
enzymes in folic acid metabolism.
a. It is used (orally and intravenously) in acute
leukemias, breast cancers, and non-Hodgkins and
T-cell lymphomas.
b. Folinic acid (leucovorin) is used to reverse MTX
toxicities and full hydration is needed to prevent
crystalluria.

3. Mercaptopurine (6-MP) inhibits purine metabolism


following its activation by hypoxanthine guanine
phosphoribosyl transferase (HGPRT).
a. Resistant cells may lack HGPRT.
b. 6-MP is used mainly in regimens for acute
leukemias.
4. Cytarabine (Ara-C) is activated by tumor cell kinases
to form a nucleotide that inhibits pyrimidine
metabolism.
a. Resistant cells may lack such kinases.
b. Ara-C is used mainly in regimens for acute
leukemias.
5. Fluorouracil (5-FU) is activated to a metabolite that
inhibits thymidylate synthase causing thymine-less
death of tumor cells.
a. Changes in this enzyme may results in resistance.
b. 5-FU is widely used, mainly for the treatment of solid

C. Plant Alkaloids (CCS Drugs)


1. Etoposide and teniposide act in late S and
early G2 phases, inhibiting topoisomerases.
a. They are used in regimens for lung (small
cell), prostate, and testicular cancers.
b. These agents cause myelosuppression.
2. Paclitaxel and docetaxel act in the M phase
to block mitotic spindle disassembly.
a. They are used in advanced breast and
ovarian cancers.
b. Significant myelosuppression occurs, but
peripheral neuropathy is distinctive.

Topoisomerase Inhibitors
o Topoisomerase I inhibitor
Topotecan
Irinotecan

Camptotheca
accuminate

Camptothecin analog

o Topoisomerase II inhibitor
Etoposide
Anthracyclins:

Doxorubicin
Idarubicin
Epirubicin
Daunorubicin

Podophyllum
peltatum

Camptothecin-Mechanism

PPO 7th edition

Antimicrotubule Agent
o Vinka alkaloid: prevent microtubule
formation
Vincristine
Vindesine
Vinblastine
Vinorelbine

o Taxane: stablize microtubule formation


Paclitaxel
Docetaxel

Cancer Chemotherapy & Biotherapy 4th edition

Structure of Microtubule

PPO 7th edition

Lancet Oncol 2005; 6: 22939

()
Treadmilling:
net growth at one end and
net shortening at the other
end
Dynamic instability:
the plus end switch
spontaneously between slow
growth and rapid shortening

()

3. Vinblastine and vincristine:


- act in the M phase to block mitotic spindle
assembly.
a. Widely used in combination regimens for
-acute leukemias,
- Hodgkins and other lymphomas,
- Kaposis sarcoma,
- neuroblastoma, and
- testicular cancer.
b. Vincristine is neurotoxic
c. Vinblastine suppresses bone marrow.

Vincristine (Oncovin)
potent vesicant (heat)

Catharanthus roseus G. Don

Mechanism: inhibit
,
microtubule assembly &
block mitosis
Metabolism: liver
Toxicity: neurotoxicity by a
peripheral, symmetric
sensorymotor, and
Dose capping: 1.4mg/m2
autonomic polyneuropathy,
Up to 2mg (due to toxicity)
phlebitis, alopecia
PPO 7th edition

Paclitaxel
Taxus brevifolia

Mechanism: enhance microtubule polymerization,


cause delay or blockage of mitosis
Toxicity: myelosuppression (non-cumulative),
hypersensitivity (Cremophor EL), symmetric
neuropathy, alopecia, myalgia, arthralgia
CDDP->Phy(24hr) => neutropenia
Phy(24hr)->Adria =>
cardiotoxicity/neutropenia/mucositis
Premedication: corticosteroids / H1+H2-receptor
antagonists
for prevention of hypersensitivity
polyvinyl chloride (PVC)!!
PPO 7th edition

D. Antibiotics
1. Bleomycin:
is a glycopeptide mixture (CCS) that alters
nucleic acid functions via free radical
formation.
a. It is used in regimens for Hodgkins and other
lymphomas and squamous cell and testicular
cancers.
b. Pulmonary toxicity, skin thickening, and by
hypersensitivity reactions are distinctive.

2. Doxorubicin and daunorubicin :


- are anthracyclines (CCNS) that intercalate
with DNA, inhibit topoisomerases, and form
free radicals.
a. Doxorubicin is widely used in breast,
endometrial, lung, and ovarian cancers and in
Hodgkins lymphoma.
b. Daunorubicin is used in leukemias.
c. Myelosuppression is marked, but
cardiotoxicity is dose limiting.

3. Other antibiotics include dactinomycin and


mitomycin.
a. Dactinomycin (CCNS) inhibits DNAdependent RNA synthesis and is used in
melanoma and Wilmstumors.
b. Mitomycin (CCNS) is biotransformed to an
alkylating agent and is used for hypoxic
tumors.
c. Both of these agents cause bone marrow
suppression.`

E. Miscellaneous Anticancer Agents.


1. Asparaginase depletes serum asparagine and
is used in auxotrophic T-cell leukemias and
lymphomas. It causes bleeding, hypersensitivity
reactions, and pancreatitis.
2. Interferons include interferon-alfa, which is used
in early-stage chronic myelogenous leukemia,
hairy cell cancers, and T-cell lymphomas.
Interferons cause myelosuppression and
neurotoxicity.
3. Monoclonal antibodies.
a. Gemtuzumab interacts with the CD33 antigen
and is used in CD33+ myloid leukemias; severe
myelosuppression is the major toxicity.

b. Rituximab interacts with a surface protein of


non-Hodgkins lymphoma cells; toxicities include
myelosuppression and nypersensitivity reactions.
c. Trastuzumab is used for breast tumors that
overexpress the HER2 protein; toxicity includes
cardiac dysfunction.
d. Alemtuzumab, which targets the CD52 antigen,
is used for treatment of B-cell chronic
lymphocytic leukemia (CLL).
4. Imatinib is a protein designed to inhibit the
abnormal tyrosine kinase created by the
Philadelphia chromosome abnormality in chronic
myelogenous leukemia (CML); toxicity includes
diarrhea, myalgia, and fluid retention.

PLATINUM COMPOUNDS
Cisplatin (cis-diaminedichlorplatinum) is an inorganic

platinum complex.
mechanism of action: DNA synthesis by formation
of intra-and interstrand cross-links with DNA molecule.
Adverse effects, toxicity:
severe vomiting
nephrotoxicity is dose-related
(acute distal tubular necrosis).
Prevention: the patients is fully hydrated by IV infusion
combined with manitol and furosemide.
hypomagnesemia
ototoxicity develops in up to 30%.
Peripheral neuropathy can be disabling.
myelosuppression

Cisplatin
is the most effective single agent in testicular
x
teratomas, but is usually given in combination with
other cytotoxic drugs.
Cisplatin has been used with some success in head
and neck
and bladder cancers -IV .

Carboplatin
is less toxic (renal toxicity or ototoxicity),
neuropathy is rare and vomiting although common,
is less severe than after cisplatin.

Oxaliplatin

HORMONES and antagonists


Hormon can cause remission in certain types of cancer
x
(breast and prostate).
Ways in which hormones can affect malignant cells:
a direct cytotoxic action on the malignant cells.
This is likely if cancer cells that are normally dependent
on a specific hormone are exposed to a high
concentration of a hormone with the opposite effect (if
a carcinoma arises from cells of the prostate that are
testosterone dependent,estrogens in large doses are
cytotoxic to the cancer)
a hormone may suppress production of the
hormones by a feedback mechanism.
Estrogens are used in the management of prostatic
and breast carcinoma

Progestogens: = megesteron,
= medroxy-progesteron acetate:
Indication:
-adenocarcinoma of the body of the uterus
- in advanced breast cancer,
- carcinoma of the kidney.
G l u c o c o r t i c o s t e r o i d s:
= are cytotoxic to lymphoid cells
= are usedwith combination with other cytotoxic
agents in treating:
lymphomas, myeloma and
to induce a remission in acute lymphoblastic
leukemia.

Hormone
a n t a g o n i s t s:
Anti-estrogens:
tamoxifen - in breast tissue competes with

endogenous estrogens for the estrogen recept


and inhibits the transcription of estrogen-respo
genes.
= is remarkably effective in some cases of
hormone-dependent breast cancer

Anti-androgens:
flutamide is used in prostate tumors
Adrenal hormone synthesis inhibitors: inh
sex hormone synthesis. Aminoglutethimide.

Aminoglutethimide
inhibits adrenal synthesis of estrogens,
glucocorticoids and mineralocorticoids
by inhibition of the enzyme producing
their common precursorpregnandione

inhibits tissue aromatase blocking


conversion
of androgens to estrogens.
Ovarian aromatase is resistant to
this inhibition, so aminoglutethimide
is only
useful in postmenopausal women.

Pharmacokinetics:
polymorphic acetylation to an inactive N-acetyl
metabolite. Fast acetylators - slow acetylators.

Adverse effects:
dizziness, lethargy are common on starting
treatment
but decline during chronic dosing
(probably due to enzyme induction).
Usage:
A. is effective in about 30% of postmenopausal
patients
with best effects on skin and breast disease.
The response of bone metastases is also good.

Interfere Protein Synthesis

o Antitubulin: vinca alkaloids and taxanes;


o Interfere the function of ribosome:
harringtonines
o Influence amino acid supply: L-asparaginase
Bind tubulin, destroy spindle to produce
mitotic arrest.

Interfere Transcription and Block RNA


Synthesis
Bind with DNA to block RNA production.
doxorubicin

Influence the Structure and Function of


DNA
o Alkylating Agent: mechlorethamine,
cyclophosphamide and thiotepa
o Platinum: cis-platinium
o Antibiotic: bleomycin and mitomycin C
o Topoismerase inhibitor: camptothecine and
podophyllotoxin

Influence Hormone Homeostasis


These drugs bind to hormone receptors to block the
actions of the sex hormones which results in inhibition
of tumor growth.
o
o
o
o
o

Estrogens and estrogen antagonistic drug


Androgens and androgen antagonistic drug
Progestogen drug
Glucocorticoid drug
gonadotropin-releasing hormone inhibitor: leuprolide,
goserelin
o aromatase inhibitor: aminoglutethimide, anastrazole

Anticancer Drugs
o Alkylating Agent
o Antimetabolite
o Antibiotics

o Alkaloid

o Hormones
o Otherscis-platinumcarboplatinlobaplatin

Alkylating Agents
o One of the frightening developments of World War I was
the introduction of chemical warfare. These compounds
were known as the nitrogen mustard gases. The nitrogen
mustards were observed to inhibit cell growth, especially
of bone marrow. Shortly after the war, these compounds
were investigated and shown to inhibit the growth of
cancer cells.

Alkylating Agents
Mechanism of Action
o Nitrogen mustards inhibit cell reproduction by binding
irreversibly with the nucleic acids (DNA). The specific
type of chemical bonding involved is alkylation. After
alkylation, DNA is unable to replicate and therefore can
no longer synthesize proteins and other essential cell
metabolites. Consequently, cell reproduction is
inhibited and the cell eventually dies from the inability
to maintain its metabolic functions.

Classification of Alkylating Agents

Bis Chloroethyl Amines

Cyclophosphamide, Chlormethine,
Chlorambucil, Sarcolysine

Nithrosoureas
Carmustine Lomustine
Ethyeneammonium or Aziridines
Thiotepa triethylene melamine
Alkysulfonates Busulfan

Resistance of Alkylating Agents


Resistance to alkylating agents has several
causes:
Membrane transport may be decreased.
The drug may be bound by glutathione (GSH) via
GSH-S-transferase or metallothioneins in the
cytoplasm and inactivated.
The drug may be metabolized to inactive species.

Adverse Effects of Alkylating Agents


o Myelosuppression is the dose-limiting adverse
effect for alkylating agents.
o Nausea and vomiting are common as are
teratogenesis and gonadal atrophy, although in
the latter cases these are variable, according
to the drug, its schedule, and route of
administration.
o Treatment also carries a major risk of
leukemogenesis and carcinogenesis.

Alkylating AgentsMustine
o Mustine must be injected intravenously because
it is highly reactive. It disappears very rapidly
from the blood, the activity of Mustine lasts only
a few minutes.
o The main indication for Mustine is in treatment of
Hodgkins disease and lymphomas, but it may
also be useful in other malignancies.

Alkylating Agents

Cyclophosphamide
Cyclophosphamide can also be given orally.
Indications

It is used in the treatment of chronic lymphocyctic


leukemia, non-Hodgkins lymphomas, breast and ovarian
cancer, and a variety of other cancers.
It is also a potent immunosuppressant, it is used in the
management of rheumatoid disorders and autoimmune
nephritis.

Adverse Effects:

Alopecia, nausea, vomiting,


hemorrhagic cystitis.

myelosuppression,

and

Alkylating AgentsNitrosoureas
Carmustine, Lomustine, Semustine
Pharmacokinetics:
Nitrosoureas are highly lipophilic and reach
cerebrospinal fluid concentrations that are
about 30% of plasma concentrations.
Indications:
Because of their excellent CNS penetration,
carmustine and lomustine have been used to
treat brain tumors.

Alkylating Agents
Phenylalanine Nitrogen Mustard
o Melphalan is a nitrogen mustard that is primarily
used to treat multiple myeloma (plasma cell
myeloma), breast cancer, and ovarian cancer.

Alkylating Agents
Alkysulfonates
Busulfan [Myleran]
Indications:
Busulfan is administered orally to treat chroic
granulocytic leukemia and other myeloproliferative
disorders.

Adverse Effects:
Busulfan produces advers effects related to
myelosuppression. It only occasionally produces
nausea and vomitting. In high doses, it produces a rare
but sometimes fatal pulmonary fibrosis, busulfan lung.

Alkylating AgentsThiotepa
Thiotepa is converted rapidly by liver mixedfunction oxidases to its active metabolite
triethylenephosphoramide (TEPA); it is active in
bladder cancer.

Antimetabolites
General Characteristics
Antimetabolites are S phase-specific
drugs that are structural analogues of
essential metabolites and that interfere
with DNA synthesis.
Myelosuppression is the dose-limiting
toxicity for all drugs in this class.

Classification of Antimetabolites
Folic acid Antagonists: MTX
Purine Antagonists: 6MP
6TG
Pyrimidine Antagonists 5FU
araC
HU

Antimetabolites
Folic Acid Antagonist
Methotrexate MTX
Mechanism of Action

o The structures of MTX and folic acid are similar.


MTX is actively transported into mammalian cells
and inhibits dihydrofolate reductase, the enzyme
that normally converts dietary folate to the
tetrahydrofolate form required for thymidine and
purine synthesis.

Antimetabolites
Folic Acid Antagonist
Methotrexate MTX

Indications
o The use of MTX in the treatment of choriocarinoma, a
trophoblastic tumor, was the first demonstration of
curative chemotherapy.
o It is especially effective for treating acute lymphocytic
leukemia and for treating the meningeal metastases of a
wide range of tumors.

Antimetabolites
Folic Acid Antagonist
Methotrexate MTX

Adverse Effects

MTX is myelosuppressive, producing severe


leukopenia, bone marrow aplasia, and
thrombocytopenia.
This agent may produce severe gastrointestinal
disturbances.
Renal toxicity may occur because of precipitation
(crystalluria) of the 7-OH metabolite of MTX.

Antimetabolites
Purine Antagonists
6-Mercapapurine 6-MP
The drugs are believed to act similarly to inhibit purine
base synthesis, although their exact mechanisms of action
are still uncertain.
Indications:
Mercaptopurine is used primarily for the maintenance of
remission in patients with acute lymphocytic leukemia and
is given in combination with MTX for this purpose.
Adverse Effects:
Well tolerate.
Myelosuppression is generally mild with thioguanine.Longterm mercaptopurine use may cause hepatotoxicity.

Antimetabolites
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Mechanism of Action
Fluorouracil is an analogue of thymine in which the methyl
group is replaced by a fluorine atom. It has two active
metabolites: 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits
thymidylate synthetases and prevents the synthesis of
thymidine, a major building block of DNA. 5-FdUTP is
incorporated into RNA by RNA polymerase and interferes
with RNA function.

Antimetabolites
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Indications
Fluorouracil is exclusively used to treat solid
tumors, especially breast, colorectal, and gastric
tumors and squamous cell tumors of the head
and neck.

Antimetabolites
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Adverse Effects
Fluorouracil may cause nausea and vomiting,
myelosuppression, and oral and gastrointestinal
ulceration. Nausea and vomitting are usually mild.
With fluorouracil, myelosuppression is more problematic
after bolus injections, whereas mucosal damage is doselimiting with continuous infusions.

Antimetabolites
Pyrimidine Antagonists
Cytarabine
Indications
Cytarabine has a narrow clinical spectrum and is primarily
used in combination with daunorubicin or thioguanine for
the treatment of acute nonlymphocytic leukemia.
Adverse Effects:
High doses of cytarabine can damage the liver, heart, and
other organs.

Antibiotics
Classification of Antibiotics:
o Adriamycin (Anthracyaline Antibiotics)
o Mitomycin C
o Bleomycin
o Actinomycin D

Antibiotics
Adriamycin and Daunorubicin
Properties:
o Adriamycin and Daunorubicin are tetracycline rings with the
sugar daunosamine. They are DNA intercalating agents that
block the synthesis of DNA and RNA.
o These agents are primarily toxic during the S phase of cell
cycle.
o These agents imparts a red tinge to the urine.
o Adramycin is used to treat acute leukemias, lymphoma, and
a number of solid tumors.

Antibiotics
Mitomycin C:
Mechanism:
Mitomycin C is an antineoplastic antibiotic that
alkylates DNA and thereby causes strand breakage
and inhibition of DNA synthesis.
Indications:
It is primarily used in combination with vinvristine as
salvage therapy for breast cancer.
Adverse Effects:
Mitomycin
produces
delays
and
prolonged
myelosuppression that preferentially affects platelets
and leukocytes.

Antibiotics
Actinomycin D:
o Actinomycin D intercalates DNA and thereby prevents
DNA transcription and messenger RNA synthesis.
o The drug is given intravenously, and its clinical use is
limited to the treatment of trophoblastic (gestational)
tumors and the treatment of pediatric tumors, such as
Wilms tumor and Ewings sarcoma.

Antibiotics
Bleomycin:
Mechanism:
o The drug has its greatest effect on neoplastic cell in
the G2 phase of the cell replication cycle.Although
bleomycin intercalates DNA, the major cytotoxicity is
believed to result from ironcatalyzed free radical
formation and DNA strand breakage.
Indications:
o It is useful in Hodgkins and non-Hodgkins
lymphomas, testicular cancer, and several other solid
tumors.
Adverse Effects:
o Bleomycin produces very little myelosuppression. The
most serious toxicities of Bleomycin are pulmonary
and mucocutaneous reactions.

Anti-Cancer Plant Alkaloids


Tubulin-Binding Agents
Vinca Alkaloids: The cellular mechanism of action of
vinca alkaloids is the prevention of microtubule
assembly, causing cells to arrest in the late G2
phase by preventing formation of mitotic filaments
for nuclear and cell division.

Anti-Cancer Plant Alkaloids


Tubulin-Binding Agents
Vinca alkaloids:
Vinblastine,vincristin, vindesine and vinorelbine are all
alkaloids derived from the periwinkle plant (Vinca rosea).

Indications:
Vinblastine is used in combination with Bleomycin
and Cisplatin for metastatic testicular tumors.
Vincristine is used in combination with prednisone
to induce remission in childhood leukemia.
Vinorelbine is used to treat non-small-cell lung
cancer and breast cancer.

Anti-Cancer Plant Alkaloids


Tubulin-Binding Agents
Paclitaxel:
Taxanes enhance all aspects of tubulin polymerization,
an action that is the opposite to that of vinca alkaloids,
but they are also cytotoxic, emphasizing the dynamic
importance of tubulin polymerization as a target for
cytotoxic drugs.
Paclitaxel, Taxotere

Anti-Cancer Plant Alkaloids


Interfere the Function of Ribosome:
Cephalotaxus Alkaloids :
Harringtonine
Homoharringtonine

Platinum Compound
Cisplatin:
Mechanism of Action:
Cisplatin binds to guanine in DNA and RNA, and
the interaction is stabilized by hydrogen bonding.
The molecular mechanism of action is unwinding
and shortening of the DNA helix.

Platinum Compound
Cisplatin:
Indications:
Cisplatin has efficacy against a wide range of
neoplasms. It is given intravenously as a first-line drug
for testicular, ovarian, and bladder cancer, and it is also
useful in the treatment of melanoma and a number of
other soild tumors.
Adverse Effect:
Cisplatin produces relatively little myelosuppression but
can cause severe nausea, vomiting, and nephrotoxicity.

Platinum Compound
Carboplatin:
Indication:
Carboplatin has a similar spectrum of activity,
but it is approved only as a second-line drug for
ovarian cancer.

Hormones
Several types of hormone-dependent cancer (especially
breast, prostate, and endometrial cancer) respond to
treatment with their corresponding hormone antagonists.
Estrogen antagonists are primarily used in the treatment
of breast cancer, whereas androgen antagonists are
used in the treatment of prostate cancer. Corticosteroids
are particularly useful in treating lymphocytic leukemias
and lymphomas.

Hormones
Estrogens:
Estrogens inhibit the effects of endogenous androgens
and androgen-dependent metastatic prostatic
carcinoma. Diethylstilbestrol is usually the agent of
choice.
Cardiac and cerebrovascular complications and
carcinoma of the male breast are potential adverse
effects.

Hormones
Progenstins:
Progestins are useful in the management of endometrial
carcinoma and back-up therapy for metastatic hormonedependent breast cancer.

Hormones
Antiestrogen: Tamoxifen
Tamoxifen is the drug of choice in postmenopausal
women with or recovering from metastatic breast cancer.
It is most effective in patients who have estrogen
receptor-positive tumors.
Tamoxifen is also used as adjunvctive therapy to
oophorectomy to leuprolide or goserelin in
premenopausal women with estrogen receptor-positive
tumors.

Hormones
Androgens:
Androgen activity in breast cancer is similar to that of
estrogens, perhaps for the same mechanistic reasons.
Virilizing effects and hepatic toxicity make them
unacceptable to most patients.
Fluoxymesterone is the most widely used agent.
Danazol has use in hematology in aplastic anemia and
congenital anemias.

Hormones
Glucocorticoids:
o They are integral components of curative therapy for
acute lymphoblastic leukemia, non-Hodgkins lymphoma,
and Hodgkins disease.
o Glucocorticoids have essential roles in the prevention of
allergic reaction, emesis control, relief of intracranial
hypertension or spinal cord compression in neurologic
complications, and pain relief.

Immunomodulating Drugs
Immunosuppressive Agents:
o Act to suppress immune mechanisms and are used to
treat autoimmune diseases or to prevent graft rejection
following tissue transplantation.
o Ciclosporin, Tacrolimus, adrenocortical hormones,
antimetabolites, alkylating agent, antilymphocyte
globulin, Mycophenolate Mofetil

Immunomodulating Drugs
Immunopotentiator :
Enhance antitumor immunity and are used to treat
neoplastic disease.
Recombinant Interferons and Cytokines.

5-Fluorourasil

Principles of chemotherapy

Metotreksat

Action sites of cytotoxic agents


6-Merkaptopurin
6-Tioguanin

Daktinomisin
Daunorubisin
Doksorubisin
Mitramisin

Sint. Purin

L-Asparaginase

RIBONUKLEOTID

DEOKSORIBO
NUKLEOTID

DNA

RNA

transkripsi

Sint. Pirimidin

Bleomisin

Hidroksiurea

ENZIM

PROTEIN

translasi

MIKRO
TUBULI

Alkilator
Sitarabin

Alkaloid Vinka
Kolkisin

Procarbazine forms free radicals; it is


used in Hodgkins lymphoma, but
may cause leukemia.

ACRONYMS
ABVD
CHOP
CMF
COP
FAC
FEC

Doxorubicin (adriamycin), bleomycin,


vinblastine, dacar-bazine.
Cyclophosphamide, doxorubicin
(hydroxydaunorubicin), vincristine
(oncovin), prednisone.
Cyclophosphamide, methotrexate,
fluorouracil.
Cyclophosphamide, vincristine
(oncovin), prednisone.
Fluorouracil, doxorubicin
(adriamycin), cyclophosphamide.
Fluorouracil, epirubicin,
cyclophosphamide.

Problems With Cancer Chemotherapy

o Drug Resistance
o Drug Toxicity

Drug Resistance

De novo Resistance

o Acquired Resistance

o Multidrug Resistance (MDR)

Drug Resistance
De novo resistance:
o

De novo resistance can be de novo genetic (i.e. the


cells are initially inherently resistant), or can arise
because drugs are unable to reach the target cells
because of permeability barriers such as the bloodbrain barrier.

Drug Resistance
Acquired Resistance:
o Acquired drug resistance may result from genomic
mutations, such as the induction or deletion of enzymes
involved in drug inactivation or drug activation,
respectively.

Drug Resistance
Multidrug Resistance (MDR):
o P-glycoprotein transports many naturally occurring drugs
out of neoplastic cells, and its induction may lead to
multidrug resistance.
o As scientific understanding of the mechanisms of drug
resistance increases, new treatments may be developed
to counteract resistance.

Drug Toxicity
o The most common toxicities of antineoplastic drugs
result from inhibition of cell replication in the bone
marrow, gastrointestinal epithelium, and hair follicles.
Many antineoplastic drugs also stimulate the
chemoreceptor trigger zone in the medulla and thereby
elicit nausea and vomiting.

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