Drugs Used in the treatment of Cancer

Drugs Used in the treatment of Cancer Pharmacology 49.222 Bill Diehl-Jones RN, PhD Faculty of Nursing and Department of Zoology Agenda • Zen Review – What is cancer • • • • • General goals in cancer treatment Targets of chemotherapy Targets of radiotherapy Breast cancer therapies Prostate cancer therapies 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 The Cell Cycle 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 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 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 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 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 Breast Cancer Treatments/Therapies 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 Exposure to Estrogen-like Compounds Confers Risk of Breast Cancer They may bind to same receptors, yield similar metabolites Mechanisms Estrogen/Estrogen-like Molecules Induce Cell-Proliferation Genes Estrogen/Estrogen-Like Metabolites Form DNA Mutations Metabolites Free Radicals OH•, O• DNA Adducts Why are they problematic? • Adducts may disrupt key regulatory pathways in ductal cells • Eg: p53, ras • Adducts can cause gene mutations: C A G T C A A G T G A T T T C T A Many Breast Cancer Therapies Depend on Estrogen Receptor Status 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 Aromatase Inhibitors A New Class of Breast Cancer Drugs NOT ER+ Dependant Estrogen from Two Sources May Initiate Breast Cancer: Exogenous Estrogen Androstenedione Testosterone Aromatase AI Estrone Estradiol Endogenous Estrogen Due to aromatase overexpression 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®) 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 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. How is Prostate Cancer Detected? • DRE • PSA A combination is best Prostate Cancer Therapies • Watch and wait – Generally a slow-growing cancer • Surgery – Surgical excision, nerve-sparing (hopefully) • Brachiitherapy – Implantation of radioactive pellets 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 Testicular Cancer Factoids • Most common cancer in men 15 – 35 • 90% cure rate if detected early • Method of detection: – Routine testicular palpation 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 Can you name the patient? Lance Armstrong • 6-time Tour de France winner (AFTER getting cancer) Responsiveness to Chemotherapy • 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 • These do NOT respond: – Thyroid, Brain CA, liver, malignant melanoma, pancreatic, cervical