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‡ Cancer is the uncontrolled growth of cells coupled with malignant
behavior, invasion and metastasis. It is caused by interaction
between genetic susceptibility and environmental toxins.

‡ Chemotherapy - treatment of a disease by chemicals that kill cells,

specifically those of micro-organisms or cancer.

‡ In popular usage, it refer to antineoplastic drugs used to treat cancer

or the combination of these drugs into a standardized treatment
regimen.

‡ The first drug used for cancer chemotherapy, in the early 20th
century, Mustard gas.
‡ Most chemotherapeutic drugs work by impairing mitosis, effectively
targeting fast-dividing cells. Some cause cells to undergo apoptosis.

‡ As chemotherapy affects cell division, tumors with high growth rates

(acute myelogenous leukemia, aggressive lymphomas) are more
sensitive to chemotherapy. Malignancies with slower growth rates
(indolent lymphomas) respond to chemotherapy modestly.

‡ Solid tumors are insensitive to chemotherapy since cell division has

effectively ceased near its center and the chemotherapeutic agent
does not reach the core of the tumor. So radiation therapy and
surgery.
‡ Chemotherapy may be given with a curative intent or it may aim to prolong life
or to palliate symptoms.

‡ Combined modality chemotherapy is the use of drugs with other cancer

treatments, such as radiation therapy or surgery. Most cancers are now
treated in this way.

‡ Combination chemotherapy involves treating a patient with a number of

different drugs simultaneously, minimizing the chances of developing
resistance to any one agent.

‡ In neoadjuvant chemotherapy (preoperative treatment) initial chemotherapy

aimed for shrinking the primary tumor, rendering local therapy (surgery or
radiotherapy) less destructive or more effective.
‡ Adjuvant chemotherapy (postoperative treatment) used when there is risk of
recurrence.

‡ Palliative chemotherapy is without a curative intent, but to decrease tumor

load and increase life expectancy.
‡ Chemotherapeutic drugs are divided in to
ß alkylating agents
ß antimetabolites
ß anthracyclines
ß plant alkaloids
ß topoisomerase inhibitors
ß other antitumour agents.
‡ Most affect cell division or DNA synthesis and function

‡ Some agents don't directly interfere with DNA, but directly targets a
molecular abnormality in certain types of cancer. Eg. monoclonal
antibodies and the tyrosine kinase inhibitors (chronic myelogenous
leukemia, gastrointestinal stromal tumors).

‡ Some drugs are used to modulate tumor cell behaviour without

directly attacking those cells. eg. Hormone treatments.
‡ Alkylating agents

² Alkylating agents add alkyl groups to many electronegative groups

present in cells or chemically modify cellular DNA.

² Cisplatin, Busulfan, Streptozotocin, mechlorethamine,

cyclophosphamide, chlorambucil, etc are alkylating agents.

‡ Anti-metabolites

² Anti-metabolites masquerade purine or pyrimidine - which are the

building blocks of DNA. They prevent these substances becoming
incorporated in to DNA during the "S" phase (of the cell cycle),
stopping normal development and division. They also affect RNA
synthesis. These drugs are the most widely used cytostats.
‡ Plant alkaloids and terpenoids

² derived from plants, block cell division by preventing microtubule

function which is vital for cell division. Eg. vinca alkaloids,
Podophyllotoxin and taxanes.

‡ Topoisomerase inhibitors

² interferes with both transcription and replication of DNA by

upsetting DNA supercoiling.

² Type I topoisomerase inhibitors include camptothecins: irinotecan

and topotecan.

² Type II inhibitors include etoposide, etoposide phosphate, and

teniposide.
‡ Anthracyclines or anthracycline antibiotics
² used to treat a wide range of cancers, including leukemias,
lymphomas, and breast, uterine, ovarian, and lung cancers.
² main adverse effects are heart damage (cardiotoxicity) and
vomiting.
² The first anthracycline discovered was daunorubicin.
‡ Monoclonal antibodies

² Monoclonal antibodies work by targeting tumour specific antigens,

enhance the host's immune response to tumour cells. Examples.
Herceptin, cetuximab, and rituximab.

‡ Hormonal therapy

² Cancer arising from certain tissues, including the mammary and

prostate glands, may be inhibited or stimulated by appropriate
changes in hormone balance.
Side-effects

Current chemotherapeutic techniques have a range of side effects,

mainly affecting the fast-dividing cells of the body.

common side-effects include (dependent on the agent):

² Pain ² Memory loss

² Nausea and vomiting ² Depression of the immune

² Diarrhea or constipation system

² Anemia ² Secondary neoplasms

² Malnutrition ² Cardiotoxicity

² Weight loss or gain ² Hepatotoxicity

² Hemorrhage ² Nephrotoxicity

² Hair loss ² Ototoxicity

Alkylating agents

‡ Alkylation is the transfer of an alkyl group from one molecule to

another. The alkyl group may be transferred as an alkyl carbocation,
a free radical, a carbanion or a carbene .

‡ Alkylating agents are classified as Nucleophilic alkylating agents and

Electrophilic alkylating agents.

‡ Nucleophilic alkylating agents

@ Deliver the equivalent of an alkyl anion.

‡ Electrophilic alkylating agents

‡ Deliver the equivalent of an alkyl cation.

‡ In medicine, alkylation of DNA is used in chemotherapy as anti-cancer

drugs to damage the DNA of cancer cells. Alkylation is accomplished
with the class of drugs called alkylating antineoplastic agents.
‡ Electrophilic alkylating agents alkylate DNA, perform as alkylating
antineoplastic agents and as chemical weapons such as mustard
gas.

‡ Alkylating agents add alkyl group that covalently bind to cellular

nucleophilic sites like bases in DNA.

² may attach alkyl groups to DNA bases, resulting in DNA being

fragmented during repair process.

² alkylating agents can cause mispairing of the nucleotides, leading

to mutation.

² cause formation of cross-bridges between atoms in the DNA, two

bases linked together by alkylating agent having two DNA binding
sites.
‡ Alkylated DNA either does not coil or uncoil properly, or cannot be
processed by enzymes.

‡ This results in inhibition of the growth of the cell, initiation of

programmed cell death or necrosis.

‡ Also mutations may be triggered, including carcinogenic mutations,

so higher incidence of cancer after exposure.

‡ Therapeutic effect - DNA damage by alkylating agents are more

detrimental to cancer cells since they generally proliferate
unrestrictively.

‡ Most alkylating agents have dose-limiting toxicities to the bone

marrow and lesser degree to the intestinal mucosa.

‡ Mechlorethamine is the first alkylating agent used in human cancer

management.
‡ The major classes of clinically useful alkylating agents are

² Alkyl Sulfonates

² Aziridines or Ethyleneimines and methylmelamines

² Nitrogen Mustards

² Nitrosoureas

² Triazenes and Imidazotetrazines

² Platinum-based chemotherapeutic drugs

‡ DNA Alkylating agents
² Alkyl sulfonates
‡ Busulfan
² Aziridines or Ethyleneimines and methylmelamines
‡ Hexamethylmelamine or altretamine
‡ Thiotepa
² Nitrogen mustards
‡ Cyclophosphamide
‡ Mechlorethamine or mustine
‡ Uramustine or uracil mustard
‡ Melphalan
‡ Chlorambucil
‡ Ifosfamide
² Nitrosoureas
‡ Carmustine
‡ Streptozotocin
² Triazenes and Imidazotetrazines
‡ Dacarbazine
‡ Temozolomide
‡ DNA Alkylating-like : Platinum-based chemotherapeutic drugs
(platinum analogues)

² Cisplatin

² Carboplatin

² Nedaplatin

² Oxaliplatin

² Satraplatin

² Triplatin tetranitrate
Clinical Pharmacokinetics/ Pharmacodynamics of alkylating agents

‡ The pharmacokinetics of the alkylating agents are highly variable

dependent on the individual agent, generally characterized by high
reactivity and short half-lives.

‡ Mechlorethamine is unstable and is administered rapidly in a running

intravenous infusion to avoid its rapid breakdown to inactive
metabolites.

‡ Chlorambucil and cyclophosphamide are stable to be given orally and

are completely absorbed from the gastrointestinal tract, while
melphalan have poor and variable oral absorption.

‡ Cyclophosphamide, ifosfamide, and dacarbazine are unusual in that

they require activation by Cyt p450 in the liver before they can
alkylate cellular constituents. The nitrosoureas also require
activation, albeit nonenzymatic.
‡ The alkylating agents form covalent bonds with a number of
nucleophilic groups present in proteins, RNA, and DNA (e.g., amino,
carboxyl, sulfhydryl, imidazole, phosphate).

‡ Under physiological conditions, the chloroethyl group of the nitrogen

mustards undergoes cyclization, with the chloride acting as a leaving
group forming an intermediate carbonium ion that attacks
nucleophilic sites.

‡ Bifunctional alkylating agents (with two chloroethyl side chains) can

undergo a subsequent cyclization to form a covalent bond with an
adjacent nucleophilic group, resulting in DNA:DNA or DNA:protein
cross links.

‡ The N-7or O-6 atoms of guanine are particularly susceptible and may
represent primary targets that determine both the cytotoxic and
mutagenic consequences of therapy.
Alkyl Sulfonates - Busulfan
² It shows nucleophilic selectivity for thiol groups, exert cytotoxicity
through protein alkylation rather than through DNA.

² has a greater effect on myeloid cells than lymphoid cells, thus its use
against chronic myelogenous leukemia.

² a cell cycle non-specific alkylating agent.

² Used in bone marrow transplantation, especially in chronic myelogenous

leukemia (CML), Chronic Lymphocytic Leukemia (CLL).

² produces DNA-DNA and DNA-protein cross linking.

² Toxicity and side effects include interstitial pulmonary fibrosis,

hyperpigmentation, seizures, hepatic and wasting syndrome,
thrombocytopenia, a condition of lowered blood platelet count and
activity.
Aziridines or Ethyleneimines and methylmelamines

‡ Aziridines are analogs of ring-closed intermediates of nitrogen

mustards and are less chemically reactive, but they have equivalent
therapeutic properties.

Altretamine (hexalen)

² Is used to treat refractory ovarian cancer. It is less toxic than

other drugs used for treating refractory ovarian cancer.

² The precise mechanism by which altretamine exerts its anti-

cancer effect is unknown.

² Side effects include nausea, vomiting, diarrhea and neurotoxicity.

ThioTEPA (N,N'N'-triethylenethiophosphoramide)

² is an organophosphorus compound , used to treat breast cancer,

ovarian cancer, and bladder cancer. It is also used as conditioning
for bone marrow transplantation.

² main toxicity is myelosuppression.

Nitrogen mustard

‡ Nitrogen mustards are nonspecific DNA alkylating agents, they form

cyclic imminium ions by attack of nitrogen on the organochloride
center. The effects are radiomimetic.

‡ Mustine, the first drug to be used as an anticancer chemotherapeutic

is nitrogen mustard.

‡ Nitrogen mustards include cyclophosphamide, chlorambucil,

uramustine, Melphalan (L-phenylalanine mustard), ifosamide, etc.

‡ One distinguishing feature of melphalan is that an amino acid

transporter influences its efficacy across cell membrane.

‡ Cyclophosphamide and ifosfamide are prodrugs that require Cyt p-

450 metabolism to release active alkylating species.
Cyclophosphamide is the most widely used alkylating agent and has
activity against a variety of tumors.
Cyclophosphamide

‡ also known as cytophosphane, is a nitrogen mustard alkylating agent,

from the oxazophorines group. It is used to treat various types of
cancer and some autoimmune disorders. It is a prodrug and is
converted in the liver to active forms that have chemotherapeutic
activity.

‡ used together with other chemotherapy agents in the treatment of

lymphomas, some forms of leukemia and some solid tumors.
‡ Cyclophosphamide is converted by mixed function oxidase enzymes
in the liver to active metabolite, like 4-hydroxycyclophosphamide that
exists in equilibrium with its tautomer, aldophosphamide.

‡ Most of the aldophosphamide is oxidised by the enzyme aldehyde

dehydrogenase (ALDH) to make carboxyphosphamide and a small
proportion of aldophosphamide is converted into phosphoramide
mustard and acrolein.

‡ Effect is due to its metabolite phosphoramide mustard that forms DNA

crosslinks at guanine N-7 positions, leading to cell death.

‡ As ALDHs are present in relatively large concentrations in bone

marrow stem cells, liver and intestinal epithelium, Cyclophosphamide
has little toxicity in these cells. ALDHs convert aldophosphamide to
carboxyphosphamide that does not give rise to the toxic metabolites.
Side-effects of cyclophosphamide

‡ Cyclophosphamide is itself carcinogenic, potentially causing

transitional cell carcinoma of the bladder as a long-term
complication. It can lower the body's ability to fight an infection. It can
cause temporary or permanent sterility. Although it is used to treat
cancer, it may increase the risk of developing other forms of cancer,
sometimes months to years after treatment.

‡ Side-effects include chemotherapy-induced nausea and vomiting

(CINV), bone marrow suppression, stomach ache, diarrhea,
darkening of the skin/nails, alopecia (hair loss), changes in color and
texture of the hair, and lethargy. Hemorrhagic cystitis is a frequent
complication, but this is prevented by adequate fluid intake and
Mesna (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl
donor and binds acrolein.
Mechlorethamine

‡ An analogue of mustard gas also known as chlormethine, mustine,

nitrogen mustard and HN2 and sold under the brand name
Mustargen, is the prototype anticancer chemotherapeutic drug.

‡ Derived from chemical warfare research and is used in chemical

warfare where it has the code-name HN2, as a powerful vesicant.

‡ As derivatized into the estrogen analogue estramustine, used to treat

prostate cancer.
Uramustine

‡ Is a derivative of nitrogen mustard and uracil.

‡ It is used in lymphatic malignancies such as non-Hodgkin's

lymphoma.

‡ It works by damaging DNA, primarily in cancer cells that

preferentially take up the uracil during rapid cycles of cell division.
The DNA damage leads to apoptosis of the affected cells.

‡ Bone marrow suppression and nausea are the main side effects.
Melphalan

‡ A phenylalanine derivative of mechlorethamine.

‡ Is used to treat multiple myeloma and ovarian cancer, and

occasionally malignant melanoma, Oral or intravenous
administration.

‡ Common side effects include Nausea and vomiting, Bone marrow

suppression and Less common side effects include Severe allergic
reactions , Scarring of lung tissue (usually only with prolonged use),
Hair loss, Rash, Itching, etc.
Chlorambucil

‡ Is mainly used in the treatment of chronic lymphocytic leukemia, can

be given orally.

‡ Side effects

² Bone marrow suppression (anemia, neutropenia,

thrombocytopenia).

² development of other forms of cancer.

² Other side effects include: Gastrointestinal Distress, Skin

reactions, Hepatotoxicity, Infertility, Central Nervous System
associated problems, etc.
Ifosfamide

‡ is given as a treatment for a variety of cancers, including:

² Testicular cancer, Breast cancer, Lymphoma (Non-Hodgkin), Soft

tissue sarcoma, Osteogenic sarcoma, Lung cancer, Cervical
cancer, Ovarian cancer, Bone cancer, etc.

‡ The delivery is intravenous

‡ Ifosfamide is often used in conjunction with Mesna to avoid internal

bleeding in the patient, in particular hemorrhagic cystitis.
Nitrosourea

‡ are lipophilic and thus can cross the blood-brain barrier, so useful in
the treatment of brain tumors such as glioblastoma multiforme.

‡ Spontaneous decomposition of the molecule yield a diazonium

hydroxide and an isocyanate. The isocyanate species generated
show nucleophilic selectivity towards sulfhydryl and amino groups,
can inhibit a number of enzymes involved in nucleic acid synthesis
and thiol balance.

‡ effective against murine tumors due to low level expression of an

enzyme responsible for repair of O-6 alkyl guanine, which is high in
humans, so the reduced clinical efficacy of nitrosoureas in humans.

‡ Examples include Carmustine, Lomustine, Ethylnitrosourea (ENU),

Streptozotocin. Some nitrosoureas (Lomustine) have been associated
with the development of interstitial lung disease.
Carmustine or BCNU

‡ m-chloro-nitrosourea compound used in the treatment of several

types of brain cancer (including glioma, glioblastoma multiforme,
medulloblastoma and astrocytoma), multiple myeloma and lymphoma
(Hodgkin's and non-Hodgkin), etc.

‡ Bone marrow and pulmonary toxicities results.

Streptozotocin

‡ Glucosamine-nitrosourea compound , discovered in a strain of the

soil microbe Streptomyces achromogenes .

‡ Particularly toxic to the insulin-producing beta cells of the pancreas,

used for treating certain cancers of the Islets of Langerhans and in
medical research to produce an animal model for Type 1 diabetes.
‡ Toxic to cells by causing damage to the DNA, though other
mechanisms may also contribute. Streptozotocin is similar enough to
glucose to be transported into the cell by the glucose transport
protein GLUT2, but is not recognized by the other glucose
transporters. So its relative toxicity to beta cells, which have
relatively high levels of GLUT2.

‡ Streptozotocin carries substantial risk of toxicity and rarely cures the

cancer, so use is generally limited to patients whose cancer cannot
be removed by surgery.
Triazenes and Imidazotetrazines

‡ Dacarbazine is a Triazene and Temozolomide an Imidazotetrazine.

Dacarbazine

‡ For treatment of various cancers, like malignant melanoma, Hodgkin

lymphoma, sarcoma, islet cell carcinoma of the pancreas, etc.

‡ Side effects include sterility, possibly permanent, birth defects to

children conceived or carried during treatment, immune suppression,
headache, fatigue and occasionally diarrhea.

‡ Experimental - Dacarbazine + Oblimersen in clinical trials for

malignant melanoma.
Temozolomide

‡ Temozolomide is an imidazotetrazine derivative of dacarbazine and

interferes with DNA replication.

‡ Acts as a prodrug , undergoes rapid chemical conversion in

circulation at physiological pH to the active compound, MTIC
(monomethyl triazeno imidazole carboxamide), a triazine derivative.

‡ Oral alkylating agent, and crosses the blood brain barrier with
concentrations in the central nervous system approximating 30% of
plasma concentrations.

‡ Used in the treatment of gliomas and melanomas and in refractory

anaplastic astrocytoma -- a type of cancerous brain tumor.

‡ Temozolomide is genotoxic, teratogenic and fetotoxic, other effects

associated with are nausea and vomiting.
Further improvement of anticancer potency

‡ combining with chloroquine - beneficial for the treatment of glioma.

‡ In laboratory studies, temozolomide killed brain tumor cells more

efficiently when along with epigallocatechin gallate (EGCG).

‡ Combining with O-6-benzylguanine which can be inhibit the enzyme

O-6-alkylguanine-DNA-alkyltransferase, that repair the damage done
by temozolomide or dacarbazine ie., methylation of DNA at the N-7 or
O-6 portions of guanine residues.
Toxicity of alkylating agents

‡ The primary dose-limiting toxicity is suppression of bone marrow

function, bone marrow toxicity involve all of the blood elements,
leukocytes, platelets, and red cells.

‡ Secondary limiting effects on the proliferating cells of the intestinal

mucosa.

‡ Other organ systems that are frequently limiting include the lungs
(pulmonary fibrosis) and the liver.

‡ Cyclophosphamide and ifosfamide can cause severe hemorrhagic

cystitis.

‡ Renal and Bladder Toxicity.

‡ Alopecia.
‡ Nausea and Vomiting- overall frequency is directly proportional to the
dose of alkylating agent.

‡ They are teratogenic and carcinogenic. Development of myeloid

leukemia, acute leukemia, solid tumors or other malignancies.

‡ Allergic Reactions- Alkylating agents covalently bind to proteins, and

these conjugates can act as haptens and produce allergic reactions.

‡ Interstitial Pneumonitis and Pulmonary Fibrosis

‡ Immunosuppression- Alkylating agents suppress both humoral and

cellular immunity .
Platinum-based chemotherapeutic drugs

‡ Platinum is the core element of the compounds cisplatin, carboplatin,

oxaliplatin, satraplatin, etc. These compounds induces cell killing
effects through the development of covalent bifunctional DNA
adducts with cellular DNA. Covalent binding to other subcellular
components including proteins, lipids, RNA, and mitochondrial DNA
occurs as well.

‡ The cell killing potential of platinum compounds was discovered by

Barnett Rosenberg et al in the mid-1960s. Clinically utilised, cisplatin
in the 1970s, carboplatin in the 1980s, oxaliplatin in the early 2000s,
and more recently, satraplatin.
Platination of cellular DNA is different from alkylation of cellular DNA.

‡ In the bifunctional adducts formed by alkylating agents with cellular

DNA, DNA has spatial flexibility relative to the covalently bound drug,
and vice-versa. The DNA that is covalently bound to the platinum
compound is fixed in space relative to the platinum core.

‡ Cytosolic inactivation of drug, which occurs at high levels of

resistance, is mediated through the glutathione detoxification
pathways and by metallothionines.

‡ The toxicity profile of these agents is pronounced and include renal

failure, peripheral neuropathy, myelosuppression, and nausea and
vomiting.
Cisplatin or cis-diamminedichloridoplatinum(II) (CDDP)
‡ Is used to treat various types of cancers, including sarcomas, some
carcinomas (e.g. small cell lung cancer, and ovarian cancer),
lymphomas and germ cell tumors.
‡ Although cisplatin is frequently designated as an alkylating agent, it
has no alkyl group and cannot carry out alkylating reactions. It is
correctly classified as alkylating-like.
‡ Platinum complexes are formed in cells, which bind and cause cross-
linking of DNA - ultimately triggering apoptosis, or programmed cell
death.
‡ Following administration, one of the chloride ligands is slowly
displaced by water (aquation). The aqua ligand in the resulting
[PtCl(H2O)(NH3)2]+ is easily displaced, and cisplatin coordinate to a
basic site in DNA. Also, the platinum cross-links two bases via
displacement of the other chloride ligands.

‡ Side effects

‡ Nephrotoxicity is a major concern. This is a dose-limiting toxicity.

‡ Neurotoxicity.

‡ Ototoxicity - may be related to ability to bind melanin in the stria

vascularis of inner ear or the generation of reactive oxygen species.

‡ Electrolyte disturbance: Cisplatin can cause hypomagnesaemia,

hypokalaemia and hypocalcaemia.
‡ Nausea and vomiting.
Carboplatin

‡ it has a bidentate cyclobutane dicarboxylate (CBDCA) moiety as its

leaving group in contrast to the more readily leaving chloro groups of
cisplatin.

‡ Used against ovarian carcinoma, lung, head and neck cancers.

‡ it has reduced side-effects compared to its parent compound

Cisplatin, particularly the elimination of nephrotoxic effects, due to
the added stability of Carboplatin in the bloodstream, which prevents
proteins from binding to it.
‡ Nausea and vomiting are less severe and more easily controlled.

‡ Have myelosuppressive effects which causes the blood cell and

platelet output of bone marrow in the body to decrease.

‡ Four times more Carboplatin is needed to achieve the same

effectiveness of Cisplatin.
Oxaliplatin
‡ Compared to cisplatin the two amine groups are replaced by
cyclohexyldiamine for improved antitumour activity. The chlorine
ligands are replaced by the oxalato bidentate derived from oxalic acid
in order to improve water solubility.

‡ It is typically administered in combination with fluorouracil and

leucovorin in a combination known as FOLFOX for the treatment of
colorectal cancer.
‡ Side-effects of oxaliplatin treatment

‡ Neuropathy, Fatigue , Nausea, vomiting, and/or diarrhea,

Neutropenia, Ototoxicity.

‡ Some patients experience allergic reaction.

‡ Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and

carboplatin.
Satraplatin

‡ Currently under investigation as treatment for advanced prostate

cancer that failed previous chemotherapy.

‡ Not yet received approval from the U.S. Food and Drug
Administration.

‡ Satraplatin is the first orally active platinum-based chemotherapeutic

drug

‡ The drug has also been used in the treatment of lung and ovarian
cancers.

Nedaplatin

‡ is a platinum compound which produces less nausea, vomiting and

nephrotoxicity.
Triplatin tetranitrate

‡ It is a trinuclear platinum coordination complex, with chloride and

amine ligands.

‡ Currently undergoing clinical trials for the treatment of human

cancer.

‡ The drug acts by forming coordinate covalent adducts with cellular

DNA.

‡ Have large dose limiting side-effects. Include diarrhea, cramps and

vomiting.
Drug Resistance and Modulation

‡ Intrinsic or acquired resistance to alkylating agents occurs that limits

the therapeutic utility of this class of anticancer drugs.

‡ Some of the factors that can contribute to the expression of

resistance to alkylating agents include:

² alterations in drug uptake or transport;

² increased repair of drug-induced nucleic acid damage;

² failure to activate alkylating agent prodrugs;

² increased scavenging of drug species by non-essential cellular

nucleophiles;

² increased enzymatic detoxification of drug species; and

² altered expression of genes coding for cellular commitment to

apoptosis.
Future Perspectives

‡ Antibody-directed enzyme prodrug therapy (ADEPT) - use of an

antibody linked to the peptidase, carboxypeptidase G-2, which
releases an active alkylator from an inactive I3-glutamyl conjugate.
By linking the peptidase to an antibody that selectively localize tumor
cell membrane will lead to local prodrug activation and cell killing.

‡ A further targeting approach delivers the gene for a cyt - P450

isoenzyme to tumors by viral vector, thereby enhancing specific
tumor cell activation of cyclophosphamide.