Anticancer Drugs

Cytotoxic drugs

Antineoplastic agents

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Principles of Cancer Chemotherapy Cancer chemotherapy strives to cause a lethal

cytotoxic event or apoptosis in the cancer cells that

can arrest a tumor’s progression.

The attack is generally directed toward DNA or against

metabolic sites essential to cell replication.

for example, the availability of purines and

pyrimidines, which are the building blocks for DNA or

RNA synthesis .

Unfortunately, most currently available anticancer

drugs do not specifically recognize neoplastic cells but,

rather, affect all kinds of proliferating cells, both

normal and abnormal.

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Cancer Treatment Strategies

Goals of treatment:

• The ultimate goal of chemotherapy is a

cure (that is, long-term, disease-free

survival). A true cure requires the

eradication of every neoplastic cell.

• If a cure is not attainable, then the goal

becomes control of the disease (stop the

cancer from enlarging and spreading) to

extend survival and maintain the best

quality of life.

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• The neoplastic cell burden is initially

reduced (debulked),either by surgery

and/or by radiation, followed by

chemotherapy, immunotherapy, therapy

using biological modifiers, or a

combination of these treatment

modalities.

• Palliation: alleviation of symptoms and

avoidance of life-threatening toxicity. In

advanced stages of cancer, the likelihood

of controlling the cancer is far from

reality.

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Treatment options of

cancer

1. Surgery:

before 1955

2.Radiotherapy:

1955~1965

3. Chemotherapy:

after 1965

4. Immunotherapy

5. Gene therapy

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Indications for Treatment • Chemotherapy is sometimes used when neoplasms are

disseminated and are not amenable to surgery.

Adjuvant Chemotherapy:

Chemotherapy may also be used as a supplemental

treatment to attack micrometastases following surgery

and radiation treatment.

Neoadjuvant Chemotherapy:

Chemotherapy given prior to the surgical procedure in

an attempt to shrink the cancer.

Maintenance Chemotherapy

chemotherapy given in lower doses to assist in

prolonging a remission.

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Tumor susceptibility and the growth cycle • Rapidly dividing cells are generally more sensitive to

chemotherapy, whereas slowly proliferating cells are less

sensitive to chemotherapy.

• In general, nondividing cells (those in the G0 phase) usually

survive the toxic effects of many of these agents.

• Cell cycle specificity of drugs: Both normal cells and tumor

cells go through growth cycles , the number of cells that are in

various stages of the cycle may differ in normal and neoplastic

tissues.

• Cell Cycle Specific: Chemotherapeutic agents that are effective

only against replicating cells (that is, those cells that are

dividing).

• Cell Cycle Nonspecific : The nonspecific drugs, although

having generally more toxicity in cycling cells, are also useful

against tumors that have a low percentage of replicating cells. 7

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Tumor growth rate:

• The growth rate of most solid tumors in vivo is

initially rapid, but growth rate usually decreases

as the tumor size increases .

• This is due to the unavailability of nutrients and

oxygen caused by inadequate`vascularization

and lack of blood circulation.

• Tumor burden can be reduced through surgery,

radiation.

Treatment regimens and scheduling

• Drug dosages are usually calculated on the

basis of body surface area, in an effort to tailor

the medications to each patient.

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Log kill phenomenon:

• Destruction of cancer cells by chemotherapeutic agents follows

first-order kinetics (that is, a given dose of drug destroys a

constant fraction of cells).

• log kill is used to describe this phenomenon. For example, a

diagnosis of leukemia is generally made when there are about

109 (total) leukemic cells.

• Consequently, if treatment leads to a 99.999-percent kill, then

0.001% of 109 cells (or 104 cells) would remain. This is defined

as a 5-log kill (reduction of 105 cells). At this point, the patient

will become asymptomatic, and the patient is in remission.

• For most bacterial infections, a 5-log (100,000- fold) reduction

in the number of microorganisms results in a cure, because the

immune system can destroy the remaining bacterial cells.

• Tumor cells are not as readily eliminated, and additional

treatment is required to totally eradicate the leukemic cell

population.

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Pharmacologic sanctuaries:

• Leukemic or other tumor cells find sanctuary in tissues

such as the central nervous system (CNS), where

transport constraints prevent certain

chemotherapeutic agents from entering.

• Patient may require irradiation of the craniospinal axis

or intrathecal administration of drugs to eliminate the

leukemic cells at that site.

• Drugs may be unable to penetrate certain areas of

solid tumors.

Treatment protocols: Combination drug

chemotherapy is more successful than single-drug

treatment in most of the cancers for which

chemotherapy is effective.

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Combinations of Drugs:

• Cytotoxic agents with qualitatively different toxicities, and with

different molecular sites and mechanisms of action, are usually

combined at full doses.

• This results in higher response rates, due to additive and/or

potentiated cytotoxic effects, and nonoverlapping host

toxicities.

• Agents with similar dose-limiting toxicities, such as

myelosuppression, nephrotoxicity, or cardiotoxicity, can be

combined safely only by reducing the doses of each.

Advantages of drug combinations:

1) Provide maximal cell killing within the range of tolerated

toxicity,

2) Effective against a broader range of cell lines in the

heterogeneous tumor population.

3) May delay or prevent the development of resistant cell lines.

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Treatment Protocols:

• Many cancer treatment protocols have

been developed, and each one is

applicable to a particular neoplastic state.

• Therapy is scheduled intermittently

(approximately 21 days apart) to allow

recovery or rescue of the patient’s immune

system, which is also affected by the

chemotherapeutic agents, thus reducing

the risk of serious infection.

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Problems associated with chemotherapy

• Cancer drugs are toxins that present a lethal threat to

the cells.

• Cells have evolved elaborate defense mechanisms to

protect themselves from chemical toxins, including

chemotherapeutic agents.

Resistance:

• Some neoplastic cells (for example, melanoma) are

inherently resistant to most anticancer drugs.

• Other tumor types may acquire resistance to the

cytotoxic effects of a medication by mutating,

particularly after prolonged administration of

suboptimal drug doses.

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• The development of drug resistance is minimized by short-term,

intensive, intermittent therapy with combinations of drugs.

• Drug combinations are also effective against a broader range of

resistant cells in the tumor population.

Multidrug resistance: Stepwise selection of an amplified gene

that codes for a transmembrane protein (P-glycoprotein for

“permeability” glycoprotein) is responsible for multidrug

resistance.

• This resistance is due to adenosine triphosphate– dependent

pumping of drugs out of the cell in the presence of P-

glycoprotein. Cross-resistance following the use of structurally

unrelated agents also occurs. For example, cells that are

resistant to the cytotoxic effects of the Vinca alkaloids are also

resistant to dactinomycin and to the anthracycline antibiotics, as well as to colchicine, and vice versa.

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Drug Resistance

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Toxicity: Therapy aimed at killing rapidly dividing cancer cells

also affects normal cells undergoing rapid proliferation (for

example, cells of the buccal mucosa, bone marrow,

gastrointestinal [GI] mucosa, and hair follicles

Common adverse effects: Most chemotherapeutic agents

have a narrow therapeutic index.

Severe vomiting, stomatitis.

Bone marrow suppression.

Alopecia.

• Vomiting is often controlled by administration of antiemetic

drugs.

• Some toxicities, such as myelosuppression that predisposes to

infection, are common to many chemotherapeutic agents.

Other adverse reactions are confined to specific agents, such as

bladder toxicity with cyclophosphamide, cardiotoxicity with doxorubicin, and pulmonary fibrosis with bleomycin.

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The duration of the side effects varies: Alopecia is transient, but the cardiac,

pulmonary, and bladder toxicities can be irreversible.

Minimizing adverse effects: Some toxic reactions may be ameliorated by interventions:

• Perfusing the tumor locally (for example, a sarcoma of the arm).

• Removing some of the patient’s marrow prior to intensive treatment and then

reimplanting.

• Promoting intensive diuresis to prevent bladder toxicities.

• The megaloblastic anemia that occurs with methotrexate can be effectively

counteracted by administering folinic acid (leucovorin).

• With the availability of human granulocyte colony–stimulating factor (filgrastim), the

neutropenia associated with treatment of cancer by many drugs can be partially

reversed.

Treatment-induced tumors: Because most antineoplastic agents are

mutagens, neoplasms (for example, acute nonlymphocytic leukemia) may arise 10 or

more years after the original cancer was cured.

Treatment-induced neoplasms are especially a problem after therapy with alkylating

agents.

Most tumors that develop from cancer chemotherapeutic agents respond well to

treatment strategies.

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13.ANTI CANCER DRUG CLASSIFICATION

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Mechanisam of Anticancer Drugs

•Alkylating agents and related compounds, which act by forming

covalent bonds with DNA and thus impeding replication.

•Antimetabolites, which block or subvert one or more of the

metabolic pathways involved in DNA synthesis.

•Cytotoxic antibiotics, Substances of microbial origin that prevent

mammalian cell division.

•Plant derivatives (vinca alkaloids, taxanes, campothecins) -most

of these specifically affect microtubule function and hence the

formation of the mitotic spindle.

•Hormones, of which the most important are steroids, namely

glucocorticoids, oestrogens and androgens, as well as drugs that

suppress hormone secretion or antagonise hormone action.

Methotrexate potently

inhibits Dihydrofolate

reductase (DHFR).

This leads to decreased

production of compounds

adenine, guanine and

thymidine and the amino

acids methionine and serine,

depletion of thymidine.

Finally depressed DNA,

RNA, and protein synthesis

and, ultimately, to cell death. FH2 = dihydrofolate; FH4 = tetrahydrofolate; dTMP = deoxythymidine monophosphate;

dUMP = deoxyuridine mono phosphate.

Antimetabolites : Folate Antagonist Methotrexate

6-Mercaptopurine

penetrates target cells

and be converted to the

nucleotide analogue.

This leads to inhibit

the first step of de novo

purine-ring biosynthesis

This results in non-

functional RNA and DNA.

Purine antagonist: 6-mercaptopurine

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5-FU = 5-fluorouracil; 5-FUR = 5-fluorouridine; 5-FUMP = 5-fluorouridine

monophosphate; 5-FUDP = 5-fluorouridine diphosphate; 5-FUTP = 5-fluorouridine

triphosphate; dUMP = deoxyuridine monophosphate; dTMP = deoxythymidine

monophosphate. 5-FdUMP = 5-fluorodeoxyuridine monophosphate.

Pyrimidine Antagonist: 5-Fluorouracil (Analogue of uracil)

5-Fluorouracil

competes with

deoxyuridine

monophosphate for

thymidylate synthase and

reduce the thymidine.

DNA synthesis

decreases due to lack of

thymidine, leading to

imbalanced cell growth.

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Gemcitabine inhibits

DNA synthesis by being

incorporated into sites in

the growing strand that

ordinarily would contain

cytosine.

Gemcitabine

diphosphate inhibits

ribonucleotide reductase,

which is responsible for

the generation of

deoxynucleoside

triphosphates required for

DNA synthesis.

Antimetabolites: Gemcitabine

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Doxorubicin and daunorubicin

bind to the sugar-phosphate

backbone of DNA. This causes local

uncoiling. Which leads to blocks

DNA & RNA synthesis and catalyzed

breakage supercoiled DNA strands,

causing irreparable breaks.

Catalyzes the reduction of free

radicals. These in turn reduce

molecular O2, producing superoxide

ions and hydrogen peroxide, which

mediate single-strand scission of

DNA.

Antibiotics: Doxorubicin and Daunorubicin

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A DNA-bleomycin-Fe2+

complex appears to

undergo oxidation to

bleomycin-Fe3+.

The liberated electrons

react with oxygen to form

superoxide or hydroxyl

radicals, which in turn

attack the phosphodiester

bonds of DNA, resulting in

strand breakage and

chromosomal aberrations.

Antibiotics: Bleomycin

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Mechlorethamine is

alkylates the N7 nitrogen of a

guanine residue in one or

both strands of a DNA

molecule. This alkylation leads

to cross-linkages between

guanine residues in the DNA

chains and/or depurination,

thus facilitating DNA strand

breakage.

Alkylation can also cause

miscoding mutations.

Alkylating Agents: Mechlorethamine

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Plant Derivatives: Vinca Alkaloids

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Taxanes: Paclitaxel

Mechanism of Action of Antiestrogen

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Flutamide, nilutamide and

bicalutamide are synthetic,

nonsteroidal antiandrogens used in

the treatment of prostate cancer.

Estrogens, such as ethinyl estradiol or

diethylstilbestrol, had been used in the

treatment of prostatic cancer. However,

they have been largely replaced by the

GnRH analogs because of fewer adverse

effects.

Estrogens inhibit the growth of prostatic

tissue by blocking the production of LH,

thereby decreasing the synthesis of

androgens in the testis.

Hormones : Estrogens In Prostatic Cancer

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Tamoxifen binds to the estrogen

receptor and the complex fails to

induce estrogen-responsive genes,

and RNA synthesis does not ensue.

The result is depletion (down-

regulation) of estrogen receptors,

and the growth-promoting effects

of the

natural hormone and other growth

factors are suppressed.

The action of tamoxifen is not

related to any specific phase of the

cell cycle.

Hormonal Antagonists: Tamoxifen

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Normal unwinding

of double helix

Irinotecan and

topotecan are

inhibit the

unwinding of

double helix

Mechanism Of Action Of Irinotecan &Topotecan

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Irinotecan and

topotecan are

semisynthetic

derivatives.These

drugs are S-phase

specific. They

inhibit

topoisomerase I,

which is essential

for the replication

of DNA in human

cells.

Mechanism Of Action Of Irinotecan &Topotecan

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Mechanism of Action of Etoposide &Teniposide

Normal catalytic

cycle of

topoisonerase

which is inhibited

by the Etoposide

and its analog,

teniposide

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Etoposide and its analog,

teniposide are semisynthetic

derivatives of the plant alkaloid,

They block cells in the late S to G2

phase of the cell cycle.

derivative of the plant

alkaloid, podophyllotoxin.

Their major target is

topoisomerase II. Binding of the

drugs to the enzyme-DNA

complex results in persistence of

the transient, cleavable form of

the complex and, thus, renders it

susceptible to irreversible double-

strand breaks

Mechanism of Action of Etoposide &Teniposide

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Mechanism of Action of L-Asparaginase

Summary of Toxicity of Chemotherapeutic Agents

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