Drugs Used in the treatment of Cancer

1. Drugs Used in the treatment of Cancer Pharmacology 49.222 Bill Diehl-Jones RN, PhD Faculty of Nursing and Department of Zoology

2. Agenda • Zen Review • What is cancer • General goals in cancer treatment • Targets of chemotherapy • Targets of radiotherapy • Breast cancer therapies • Prostate cancer therapies

3. Characteristics of Cancer Cells • The problem: • Cancer cells divide rapidly (cell cycle is accelerated) • They are “immortal” • Cell-cell communication is altered • They can disrupt normal, healthy tissues

4. The Cell Cycle

6. Anticancer Drugs • Some Solutions • Most cancer chemotherapies are designed to “hit” cell replication • A problem: • This approach is non-specific • Most cancer chemotherapies kill cancer cells only slightly faster than normal cells

7. Targets of Anticancer Drugs: Inhibitors of DNA Synthesis (Mercaptopurine, Methotrexate) STOP Inhibitors of DNA Function (Doxorubicin, Cisplatin) STOP STOP Inhibitors of DNA Replication (Cytochalasin, Vincristine) Protein

8. The Goal of Cancer Treatments • Curative • Total irradication of cancer cells possible? • The concept of “log kill” • If 109 cells present, and tmt kills 99.999%, then 0.001% left • This is a 5-log kill • Palliative • Alleviation of symptoms • Avoidance of life-threatening toxicity

9. Cell Cycle-Dependant vs. Cell-Cycle Independent Drugs • Some drugs kill cancer cells only at certain phases of the cell cycle: • Eg: Cytochalsin • Works only when a high ppn of cells are dividing • Some drugs work throughout cell cycle: • Eg: Cisplatin

10. Some General Chemotherapy Concepts • Most drug therapies are combination • Eg: for ALL • “POMP”: Prednisone, Oncovin, Methotrexate, Purethinol • Most chemotherapeutics have very low Therapeutic Indices • Some treatments themselves may induce tumors

11. Breast Cancer Treatments/Therapies

12. Hormonal Theory of Breast Cancer • Reproductive risk factors include: • Early puberty, late menarche, short duration of breast feeding, nulliparity, delayed child birth • Theory: • prolonged exposure to estrogen may initiate breast cancer

13. Exposure to Estrogen-like Compounds Confers Risk of Breast Cancer They may bind to same receptors, yield similar metabolites

14. Metabolites Free Radicals Mechanisms Estrogen/Estrogen-like Molecules Induce Cell-Proliferation Genes Estrogen/Estrogen-Like Metabolites Form DNA Mutations OH•, O•

15. G G C C A T T G C A A T T T A A T DNA AdductsWhy are they problematic? • Adducts may disrupt key regulatory pathways in ductal cells • Eg: p53, ras • Adducts can cause gene mutations:

16. Many Breast Cancer Therapies Depend on Estrogen Receptor Status

17. Blocking Estrogen Receptors • Principle drug is TAMOXIFEN • Competes with estradiol for binding sites • Works in ER+ cancers • Often used in breast cancers which have metastasized to bone • May cause pain in affected site: a GOOD sign! • May cause eye damage

18. Aromatase Inhibitors A New Class of Breast Cancer Drugs NOT ER+ Dependant

19. Estrogen from Two Sources May Initiate Breast Cancer: Exogenous Estrogen Androstenedione Testosterone AI Aromatase Estrone Estradiol Endogenous Estrogen Due to aromatase overexpression

20. Aromatase Inhibitors • While Tamoxifen blocks a tumor’s abitlity to use estrogen, AI’s reduce the amount of estrogen in the body • Three AI’s currently approved: • Anastrazole (Arimidex®) • Exestane (Aromasin®) • Letrozole (Femara®)

21. The Bottom Line • A major study of AI’s: • Breast cancer survivors taking letrozole after completing 5 years tamoxifen theraoy had significantly lower recurrence of breast cancers than women NOT on letrozole

22. Prostate Cancer • “It doesn’t matter who you are … if you are male and live long enough, you WILL get prostate cancer” • Bill Jones Sr.

23. How is Prostate Cancer Detected? • DRE • PSA A combination is best

24. Prostate Cancer Therapies • Watch and wait • Generally a slow-growing cancer • Surgery • Surgical excision, nerve-sparing (hopefully) • Brachiitherapy • Implantation of radioactive pellets

25. A Cancer Case Study • HPI: • A 25 yo male athlete presents with severe cough, SOB; c/o a painful R. testicle • O/E: • Non-encapsulated mass in testes; masses detected in abdomen, lungs and brain • Dx: • Metastatic testicular cancer (choriocarcinoma, 40% embryonal, 1% teratoma

26. Testicular Cancer Factoids • Most common cancer in men 15 – 35 • 90% cure rate if detected early • Method of detection: • Routine testicular palpation

27. Treatment • Surgical excision of testicle • Surgery to remove 2 cancerous lesions on brain • Chemotherapy: • 1 round of BEP (bleomycin, etoposide, platinol) • 3 rounds of VIP (Ifostamide, etoposide, platinol) • Period of treatment: • October – December, 1996

28. Can you name the patient?

29. Lance Armstrong • 6-time Tour de France winner (AFTER getting cancer)

30. These Cancers Respond: Hodgkins lymphoma ALL Choriocarcinoma Wilm’s tumor Testicular, other germ line ca’s These may respond: Breast, ovarian, endometrial, myeloma, large intestine, esophageal CA’s Responsiveness to Chemotherapy • These do NOT respond: • Thyroid, Brain CA, liver, malignant melanoma, pancreatic, cervical