1. School of Pharmacy, University of Nizwa
Anticancer Drugs
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture 15
December 03, 2011

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
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
Thus, while a tumor sensitive to one alkylating agent is usually sensitive to another, cross-resistance within the group does not necessarily occur
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. 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

8. 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

9. 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
Methotrexate: Pharmacokinetics
Cirrhosis is poor liver function; interstitial pneumonia is a form of lung disease; Vasculities: inflammatory destruction of blood vessels
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

10. 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, incorporation of thiopurines synthesis, incorporation of thiopurines into nucleic acids and interference with purine interconversions

11. 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

12. 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

13. 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

14. Monoclonal Antibodies: Bevacizumab
Monoclonal antibodies have become an active area of drug development for anticancer therapy, 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

15. Miscellaneous Agents: Cisplatin
Most effective single agent in testicular teratomas, given in combination with various other cytotoxic drugs
In carcinoma of the ovary it can be combined with doxorubicin and cyclophosphamide and is more effective than a single alkylating agent
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, hypomagnesemia, ototoxicity, myelosuppression, peripheal neuropathy

16. Miscellaneous Agents: Procarbazine
Its main use is in treating Hodgkin´s disease
Procarbazine is given daily by mouth
Mechanism of Action : Precise mode of action is unknown but it depresses DNA synthesis and combines with DNA, decreasing its viscosity and causing chromosome breaks
Adverse Effects: Leukopenia and thrombocytopenia occur after days. Nausea and vomiting occur frequently but are less prominent after repeated dosage