School of Pharmacy, University of Nizwa Anticancer Drugs Course Coordinator Jamaluddin Shaikh, Ph. D. School of Pharmacy, University of Nizwa Lecture 15 April 08, 2013

Principles of Cancer Chemotherapy Cancer chemotherapy strives to cause a lethal cytotoxic event or apoptosis in the cancer cell 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 that are the building blocks for DNA or RNA synthesis Ideally, anticancer drugs should interfere only with cellular processes that are unique to malignant cells Strive: To exert much effort or energy

Anticancer Drugs Alkylating agents: Cyclophosphamide, chlorambucil, dacarbazine, busulfan, mechloethamine Antimetabolites: Folic acid analogs: Methotrexate Pyrimidine analogs: 5-Fluorouracil, cytarabine Purine analogs: 6-Mercaptopurine, 6-Thioguanine Antimitotic agents: Vincristine, vinblastine, paclitaxel Podophyllin Derivatives: Etoposide, teniposide Antibiotics: Dactinomycin, doxorubicin, bleomycin Enzymes: L-Asparaginase Hormones and related agents: Prednisolone, tamoxifen, estrogens, leuprolide, flutamide Monoclonal antobodies: Bevacizumab, rituximab Miscellaneous: Cisplatin, hydroxyurea, procarbazine

Alkylating Agents Alkylating agents are particularly effective when cells are dividing rapidly but they are not phase specific They combine with DNA of both malignant and normal cells and thus damage not only malignant cells but dividing normal cells, especially those of the bone marrow and the gastrointestinal tract The alkyl groupings on these drugs are highly reactive, so that although their most important action is on DNA they also combine with susceptible groups in cells and in tissue fluids An abnormal new growth of tissue in animals or plants phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase

Alkylating Agents: Mechanism of Action Alkylating agents forms covalent linkages by alkylation of various nucleophilic moieties such as PO4, hydroxyl, carboxyl groups. The chemotherapeutic and cytotoxic effects are directly related to the alkylation of DNA The tightly bound DNA strands are then unable to separate and cannot act as templates for RNA production or form new DNA

Alkylating Agents: Adverse Effects Bone marrow depression with leukopenia and thrombocytopenia Severe nausea and vomiting Teratogenicity Leukopenia: decrease in the number of white blood cells ; Teratogenicity: ability to cause birth defects

Antimetabolites Antimetabolites are structural analogs of cellular metabolites with which they compete It was hoped that it would be possible to find and block selectively metabolic pathways that were unique to malignant cells. This hope has not been fulfilled, and the pathways blocked by antimetabolites also occur in normal cells, thus their selectivity for malignanat cells is only partial They are usually phase specific as their action is usually confined to specific steps in the synthesis of nuclear material Malignant: An abnormal new growth of tissue in animals or plants

Folic Acid Analogs Methotrexate (MTX) is the drug of choice for choriocarcinoma Used in acute lymphatic leukemia, lymphomas and several solid tumors including osteogenic sarcoma, epidermoid carcinoma of head and neck and some bronchial carcinomas Choriocarcinoma is a quick-growing form of cancer that occurs in a woman's uterus Lymphoma is a cancer in the lymphatic cells of the immune system Osteosarcoma is a cancerous (malignant) bone tumor that usually develops during the period of rapid growth that occurs in adolescence

Methotrexate: Mechanism of Action Folic acid is required in the synthesis of thymidylic acid and purine nucleotides and so ultimately for the production of DNA MTX resembles folic acid and competes with it for the active site of dihydrofolate reductase. The affinity of methotrexate for this site is 100 000 times greater than that of dihydrofolate By blocking this step, MTX prevents nucleic acid synthesis and causes cell death

Methotrexate: Adverse Effects Myelosuppresion Nausea and vomiting Cirrhosis: chronic low-dose administration can cause chronic active hepatitis and cirrhosis, interstitial pneumonitis and osteoporosis Renal dysfunction, acute vasculitis, seizures Cirrhosis is poor liver function; interstitial pneumonia is a form of lung disease; Vasculities: inflammatory destruction of blood vessels

Methotrexate: Pharmacokinetics Given orally or intravenous or intramuscular injection Enters normal and malignant cells via an energy-dependent carrier-mediated transport process, as does folate About 80-95% of the drug undergoes renal excretion Both filtered and undergoes active tubular secretion into the urine

Purine Analogs 6-Mercaptopurine (6MP) is a purine antimetabolite It is effective in the treatment of acute leukemias, especially in children, and as an immunosuppressant Mechanism of Action: 6MP blocks DNA synthesis, probably through inhibition of de novo purine synthesis

Pyrimidine Analogs 5-Fluorouracil (5FU) is useful in the treatment of carcinomas of breast, ovary, esophagus, colon and skin It is the most effective cytotoxic agent used in treating adenocarcinoma of the gastrointestinal tract Mechanism of Action: 5FU is activated by anabolic phosphorylation to form 5-fluorouridine monophosphate which is incorporated into RNA inhibiting its function Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue

Vinca Alkaloids Two alkaloids, vinblastine and vincristine, have been isolated from the Madagascan periwinkle plant Despite their close structural relationship they differ in their clinical spectrum and toxicity Vinblastine is used in the treatment of testicular cancer and Hodgkin´s disease Vincristine is used in breast cancer, lymphomas and also in the initial treatment of acute lymphoblastic leukemia Hodgkin's lymphoma (Hodgkin's disease) is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes Lymphoma is a cancer of the lymphocytes, a type of cell that forms part of the immune system lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts Iimmature lymphocytes)

Vinca Alkaloids: Mechanism of Action Bind to tubulin, a protein that forms the microtubules that are essential for the formation of the spindle that separates the chromosomes during mitosis In the absence of an intact mitotic spindle, the chromosomes may disperse throughout the cytoplasm or may clump in unusual groupings Have other actions on cell metabolism including inhibition of nucleic acid and protein synthesis

Podophyllin Derivatives Podophyllin is extracted from the American mandrake or May apple Etoposide is one of the most active drugs against small cell lung cancer and is used in combination therapy It is also used in lymphomas, testicular teratomas and trophoblastic tumors Tropohoblasts are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta

Podophyllin Derivatives: Mechanism of Action It blocks cells in the late S-G2 phase Its major target is topoisomerase II. It forms a ternary complex with topoisomerase II and DNA but the strand passage and resealing of the break that normally follow topoisomerase binding to DNA are inhibited by the drug

Antibiotics: Doxorubicin Used in acute leukemia, lymphomas, sarcomas and a wide range of carcinomas Mechanism of Action: Intercalation between adjacent base pairs in DNA, thus inhibiting further nucleic acid synthesis and leading to fragmentation of DNA and inhibition of DNA repair Adverse Effects: Cardiotoxicity Bone marrow suppression Nausea and vomiting Extravasation causing severe tissue necrosis Sarcoma is a cancer that arises from transformed cells of mesenchymal origin DNA intercalation is the insertion of a small ligand or fragment between two adjacent base pairs in the DNA strand, forming stable sandwich-like structures

Enzymes: L-Asparaginase Used to treat childhood acute lymphocytic leukemia in combination with prednisone Catalyses the deamination of asparagine to aspartic acid and ammonia. Some neoplastic cells require an external source of asparagine, because of their limited capacity to make sufficient L-asparagine to support growth and function L-asparaginase hydrolyses blood aspargine and thus deprives the tumor cells of this nutrient required for protein synthesis Deamination is the removal of an amine group from a molecule

Hormones Sex hormones or their antagonists are most effective in tumors arising from cells that are normally hormone dependent, namely breast and prostate. A hormone may have a direct cytotoxic action on the malignant cell. For example, cells of the prostate are testosterone dependent, if a carcinoma arises from these cells, estrogens in large doses are cytotoxic to the cancer

Monoclonal Antibodies: Bevacizumab Monoclonal antibodies have become an active area of drug development for anticancer therapy and other nonneoplastic diseases, because they are directed at specific targets and often have fewer adverse effects. They are created from B lymphocytes Mechanism of Action: Attaches to and stops vascular endothelial growth factor (VEGF) from stimulating the formation of new blood vessels. Without new blood vessels, tumours do not receive oxygen and essential nutrients necessary for growth and proliferation Adverse Effects: hypertension, proteinuria

Miscellaneous Agents: Cisplatin Most effective single agent in testicular teratomas, given in combination with various other cytotoxic drugs When combined with high-dose bleomycin and vinblastine, a remission rate of 70% is achievable In carcinoma of the ovary it can be combined with doxorubicin and cyclophosphamide and is more effective than a single alkylating agent Its use has resulted in the cure of many previously fatal germ cell tumors It has been used with some succes in head and neck and bladder cancers  

Cisplatin: Mechanism of Action Mechanism of Action: Cytotoxicity results from selective inhibition of tumor DNA synthesis by formation of intra- and interstrand cross-links in the DNA molecule Adverse Effects: Severe vomiting Nephrotoxicity is dose-related and dose limiting. It causes acute distal tubular necrosis Clinically significant hypomagnesemia Ototoxicity develops in up to 30% of patients Myelosuppression Peripheal neuropathy