1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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 times greater than that of dihydrofolate
By blocking this step, MTX
prevents nucleic acid synthesis
and causes cell death

10. 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

11. 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

12. 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

13. 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

14. 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)

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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