ANTI-CANCER DRUGS AND THEIR

MECHANISM OF ACTION

Cancer

Cancer is a disease in which the cells divide and grow uncontrollably and rapidly forming tumors.

Cancer is thought to be caused by tobacco use, certain infections, radiation, lack of physical activity, obesity and by the interaction between genetic susceptibility and environmental toxins.

There are over 200 different known cancers that afflict humans

Chemotherapy

Chemotherapy is the treatment of cancer with one or more cytotoxic antineoplastic drugs . Traditional chemotherapeutic agents act by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that chemotherapy also harms cells that divide rapidly under normal circumstances.

Targeted therapyThis results in the most common side-

effects of chemotherapy: myelosuppression (decreased production of blood cells), mucositis (inflammation of the lining of the digestive tract) and alopecia (hair loss).

Some newer anticancer drugs (monoclonal antibodies) are not indiscriminately cytotoxic, but rather target proteins that are abnormally expressed in cancer cells and that are essential for their growth. Such treatments are often referred to as targeted therapy

Types of anticancer drugsAccording to the source of drugs,the majority

of chemotherapeutic drugs can be divided in to Alkylating agents, Antimetabolites, Antibiotics, Plant alkaloids, Topoisomerase inhibitors and Other antitumour agents.Some newer agents do not directly interfere

with DNA. These include monoclonal antibodies and the new tyrosine kinase inhibitors

Mechanism of anticancer drugsBlock nucleic acid (DNA, RNA)

biosynthesis

Directly destroy DNA and inhibit DNA

reproduction

Interfere transcription and block RNA

synthesis

Interfere protein synthesis and function

Influence hormone homeostasis

Alkylating agents

Alkylating agent used in cancer treatment attaches an alkyl group to DNA. It forms a covalent bond with the nucleophilic substanceThe nitrogen at position 7(N7) of guanidine residues in DNA is strongly nucleophilic and is especially susceptible.Other molecular sites such as N1 and N3 of adenine and N3 of cytosine may also be effected.It lead to

Cross linking of bases Abnormal base pairing & DNA strand breakage

Antimetabolites Antimetabolites are structurally

related to normal componente of DNA. They prevent these substances from becoming incorporated in to DNA during the "S" phase of the cell cycle by competing with the purines and pyrimidines in DNA or RNA synthesis which in turn stops the normal development and division.

Methotrexate(Abitrexate®)

Methotrexate is the most widely used antimetabolite in cancer chemotherapy. It mainly acts by inhibiting the enzyme dihydro folate reductase(DHFR),which is essential in the conversion of folate to THF and lack of the co enzyme THF leads to inhibition of DNA synthesis

6-Mercaptopurine(Purinethol®)

6-Mercaptopurine is an analogue of purine inhibits purine nucleotide synthesis and metabolism and is highly effective anticancer drug.

It is a purine analogue of the nucleobase guanine. It incorporates into DNA during the synthesis phase (S-phase) of the cell resulting in the DNA synthesis inhibition

Tioguanine

5-Fluorouracil(Adrucil®)

5-Fluorouracil is an analogue of uracil(pyrimidine) that lead to the inhibition of DNA. It acts as a thymidylate synthase inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication

Hydroxyurea(Hydrea®)

It is an antineoplastic drug that reduces the production of deoxyribonucleotides through the inhibition of the enzyme ribonucleotide reductase that catalyzes the formation of deoxyribonucleotides from ribonucleotides

Plant alkaloids

Mitotic spindles are very important because they help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division

Vincristine

Vinca alkaloids-Vinblastine (Velban®), Vincristine (Oncovin®)Binds to the microtubular protein

tubulin in a dimeric formThe drug-tubulin complex adds to the

forming end of the microtubules to terminate assembly

Depolymerization of the microtubules occurs

Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation

Topoisomerase inhibitors

Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling.

Some type I topoisomerase inhibitors include camptothecins: irinotecan and topotecan.

Examples of type II inhibitors include podophyllotoxins,

AntibioticsActinomycin

It is isolated from soil bacteria of the genus Streptomycescell biology, Actinomycin D is shown to have the ability to inhibit transcription. It does this by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase

Anthracyclines

Anthracyclines are a class of drugs (CCNS or cell-cycle non-specific)[1] used in cancer chemotherapy derived from Streptomyces bacterium. nhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.[6] Inhibits topoisomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication.

DactinomycinBinds to double stranded DNA through

intercalation between adjacent guanine-cytosine base pairs

Inhibits all forms of DNA-dependent RNA synthesis

Binds to DNA through an antibiotic-Mg2+

complexThis interaction interrupts DNA-directed RNA

synthesis

Plicamycin

Bleomycin

It is a drug used in cancer chemotherapy. It is an anthracycline antibiotic Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription

Bleomycin acts by induction of DNA strand breaks

Doxorubicin(Adriamycin®)

Hormone therapyAromatase inhibitors

Aromatase inhibitors are an important class of drugs used for the treatment of breast cancer

At menopause, estrogen production in the ovaries ceases, but other tissues continue to produce estrogen through the action of the enzyme aromatase. When the action of aromatase is blocked, estrogen levels in post-menopausal women can drop to extremely low levels, causing growth arrest and/or apoptosis of hormone-responsive cancer cells

MONOCLONAL ANTIBODIES

Monoclonal antibodies such as Rituximab and Trastuzsumab are also used in the cancer chemotherapy.

This antibodies activate the host immune mechanism and kills the cancer cells.

RADIOACTIVE ISOTOPES

Radioactive isotopes are used in the treatment of certain tumours by their property of producing ionization in the cells,thereby causing cell destruction.

Eg.Radioactive Iodine is used in thyroid carcinoma

Some drugs areCell Cycle Nonspecific Agents (CCNSA) drugs that are active throughout the cell cycle

Alkylating Agents Antibiotics

Cell Cycle Specific Agents (CCSA) drugs that act during a specific phase of the cell cycle S Phase Specific Drug: Aantimetabolites, Topoisomerase Inhibitors M Phase Specific Drug: Vinca Alkaloids, Taxanes G2 Phase Specific Drug: Bbleomycin

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