Pharmacology of Antineoplastic Agents

1. Pharmacology of Antineoplastic Agents Outline of Lecture Topics: • Background • Antineoplastic Agents • a. Cell Cycle Specific (CCS) • b. Cell Cycle Non-Specific (CCNS) • c. Miscellaneous (e.g., antibodies) • Mechanisms of action • Side Effects • Drug Resistance

2. Cancer Therapeutic Modalities Surgery Radiation Chemotherapy 1/3 of patients without metastasis Respond to surgery and radiation. If diagnosed at early stage, close to 50% cancer could be cured. 50% patients will undergo chemotherapy, to remove micrometastasis. However, chemotherapy is able to cure only about 10-15% of all cancer patients. Cancer Chemotherapy Chapter 55. B.G. Katzung

3. Cancer Chemotherapy Chapter 55. B.G. Katzung

4. Cancer Chemotherapy C. Malignancies which respond favorably to chemotherapy: choriocarcinoma, Acute leukemia, Hodgkin's disease, Burkitt's lymphoma, Wilms' tumor, Testicular carcinoma, Ewing's sarcoma, Retinoblastoma in children, Diffuse histiocytic lymphoma and Rhabdomyosarcoma. D. Antineoplastic drugs most effective against rapidly dividing tumor cells because most inhibit cell division.

5. The Main Goal of Antineoplastic Agents IS to eliminate the cancer cells without affecting normal tissues (the concept of differential sensitivity).  In reality, all cytotoxic drugs affect normal tissues as well as malignancies - aim for a favorable therapeutic index (aka therapeutic ratio). LD50 ----- ED50 Therapeutic Index = A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50). Cancer Chemotherapy Chapter 55. B.G. Katzung

6. The effects of tumor burden, scheduling, dosing, and initiation/duration of treatment on patient survival. Untreated patients Infrequent scheduling of treatment courses. Prolongs survival but does not cure. More intensive and frequent treatment. Kill rate > growth rate. Early surgical removal of the primary tumor decreases the tumor burden. Chemotherapy will remove persistant secondary tumors. Cancer Chemotherapy Chapter 55. B.G. Katzung

7. Antineoplastic Agents Cancer Chemotherapy Chapter 55. B.G. Katzung

8. Cell Cycle and Cancer. Normal and Cancer cells must traverse before and during cell division. Differentiation 2% Synthesis of cellular Components needed For Mitosis 19% Synthesis of cellular Components needed For DNA synthesis. Replication of DNA genome 40% 39% CCS CCNS Cancer Chemotherapy Chapter 55. B.G. Katzung

9. Cancer Chemotherapy Chapter 55. B.G. Katzung

10. Structure of Major Alkylating Agents

11. Alkylating Agents: General Mechanism of Action E.g., Mechlorethamine (Nitrogen Mustards) Cancer Chemotherapy Chapter 55. B.G. Katzung

12. Cyclophosphamide (Alkylating agent) Inactive Aldophosphamide 4-Hydroxycyclophamide Breast, ovarian, CLL, soft tissue sarcoma, WT, neuroblastoma Cancer Chemotherapy Chapter 55. B.G. Katzung

13. A. Alkylating agents

14. A. Alkylating agents

15. A. Alkylating agents

16. Summary Cancer Chemotherapy Chapter 55. B.G. Katzung

17. B. Natural Products 1. Antimitotic Drugs 2. Antimitotic Drugs

18. 3. Epipodophyllotoxins (These are CCS) Accumulation of single- or double-strand DNA breaks, the inhibition of DNA replication and transcription, and apoptotic cell death.

19. 4. Antibiotics (CCS) Cancer Chemotherapy Chapter 55. B.G. Katzung

20. 5. Enzymes: L-asparaginase Cancer Chemotherapy Chapter 55. B.G. Katzung

21. C. Antimetabolites (Folic acid analog) MTX polyglutamates Are selectively retained In tumor cells. An essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA. To function as a cofactor folate must be reduced by DHFR to THF. Reduced Folate Carrier protein Methotrexate Kills cells during S-phase Cancer Chemotherapy Chapter 55. B.G. Katzung

23. 6. Drug Resistance • One of the fundamental issue in cancer chemotherapy is the development of cellular drug resistance. It means, tumor cells are no longer respond to chemotherapeutic agents. For example, melanoma, renal cell cancer, • brain cancer often become resistant to chemo. • A few known reasons: • Mutation in p53 tumor suppressor gene occurs in 50% of all tumors. This leads to resistance to radiation therapy and wide range of chemotherapy. • Defects in mismatch repair enzyme family. E.g., colon cancer no longer respond to fluoropyrimidines, the thiopurines, and cisplatins. • Increased expression of multidrug resistance MDR1 gene which encodes P-glycoprotein. Enhanced drug efflux and reduced intracellular accumulation. Drugs such as athracyclines, vinca alkaloids, taxanes, campothecins, even antibody such as imatinib. Cancer Chemotherapy Chapter 55. B.G. Katzung

24. Summary • The main goal of anti-neoplastic drug is to eliminate the cancer cells without affecting normal tissues. • Log-Kill Hypothesis states that a given therapy kills a percentage of cells, rather then a constant number, therefore, it follows first order kinetics. Aim for a favorable therapeutic index. • Early diagnosis is the key. • Combination therapy and adjuvant chemotherapy are effective for small tumor burden. • Two major classes of antineoplastic agents are: • a. Cell Cycle Specific and • b. Cell Cycle Non-Specific agents • Because chemotherapeutic agents target not only tumor cells, but also affect normal dividing cells including bone marrow, hematopoietic, and GI epithelium. Know what side effects are. • Drug resistance is often associated with loss of p53 function, DNA mismatch repair system, and increased MDR1 gene expression. Cancer Chemotherapy Chapter 55. B.G. Katzung