NURS 2343: PathoPharmacology I Lecture 14 Chapters 101-103 Mark L. Winter, Ph.D., DABAT, FAACT Texas Poison Center Network – Galveston University of St. Thomas Cancers • Most common cancers: – Solid tumors of the breast, lung, prostate, colon, and rectum – Low growth fraction and respond poorly to drugs • Rarer cancers: – Lymphocytic leukemia, Hodgkin’s disease, certain testicular cancers – High growth fraction and respond well to drugs Basic Principles of Cancer Chemotherapy • Cancer: – unregulated cellular proliferation • Treatment modalities: – Surgery – Radiation – Drug therapy • Treatment of choice for disseminated cancers (leukemia, disseminated lymphomas, widespread metastases) Basic Principles of Cancer Chemotherapy • Drug classes: – – – – Cytotoxic agents Hormones and hormone antagonists Biologic response modifiers Targeted drugs Tissue Growth and Chemotherapy • Chemotherapy drugs are more toxic to tissue with high growth fraction: – – – – – Bone marrow Skin Hair follicles Sperm Gastrointestinal tract Obstacles to Successful Chemotherapy • Toxicity to normal cells • Cure requires 100% cell kill – Kinetics of drug-induced cell kill – Host defenses contribute little to cell kill – When should treatment stop? More Obstacles to Successful Chemotherapy • • • • • Absence of truly early detection Solid tumors respond poorly Drug resistance Heterogeneity of tumor cells Limited drug access to tumor cells Strategies for Achieving Maximum Benefits From Chemotherapy • Intermittent chemotherapy – allows normal cells to recover and re-populate • Combination chemotherapy – – – – Benefits of drug combinations Suppression of drug resistance Increased cancer cell kill Reduced injury to normal cells • Optimizing dosing schedules Major Toxicities of Cancer Chemotherapy • Bone marrow suppression: – Neutropenia – Thrombocytopenia – Anemia • Digestive tract injury: – – – – Stomatitis Nausea Vomiting Diarrhea infection bleeding Major Toxicities of Cancer Chemotherapy • • • • • Alopecia Hyperuricemia Reproductive toxicity Local injury from extravasation of vesicants Unique toxicities: – Heart – Kidneys – Peripheral nerves • Carcinogenesis Making the Decision to Treat • Benefits of treatment must outweigh risks • Patient must be given some idea of the benefits of proposed therapy • One of these three should be possible: – Cure – Prolongation of life – Palliation Cytotoxic Anticancer Drugs • Largest class of anticancer drugs • Most often used • Act directly on cancer cells and healthy cells to cause their death • About 50% of cytotoxic anticancer drugs are cell phase specific • Subdivided into eight major groups Anticancer Drugs • Cytotoxic drugs: – – – – – – – – Alkylating agents Platinum compounds Antimetabolites Hypomethylating agents Antitumor antibiotics Mitotic inhibitors Topoisomerase inhibitors Miscellaneous cytotoxic drugs Cell-Phase Specificity • Sequence of events that a cell goes through from one mitotic division to the next • Cell-cycle phase–specific drugs: – Toxic only to cells that are in a particular phase – Must be in the blood continuously over a long time – Cell-cycle phase–specific drugs do not harm “resting” cells. • Cell-cycle phase–non-specific drugs – Can act during any phase of the cell cycle Toxicity • Many anticancer drugs are toxic to normal tissues, especially tissues with high growth fraction: – – – – Bone marrow Hair follicles GI epithelium Germinal epithelium Dosage, Handling, and Administration • Antineoplastic drugs are often: – Mutagenic – Teratogenic – Carcinogenic • Direct contact can result in local injury • Extravasation of vesicants: – Carmustine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, mechlorethamine, mitomycin, plicamycin, streptozocin, vinblastine, vincristine 1. Alkylating Agents • • • • • Highly reactive compounds Cells are killed by the alkalization of DNA Cell-cycle phase–non-specific agents Drug resistance is common Toxicities: – Occur in tissues with high growth fraction • Bone marrow, hair follicles, GI mucosa, and germinal epithelium Classes of Alkylating Agents • Nitrogen mustards (6) – Cyclophosphamide • Nitrosoureas (3) – Carmustine • Other – Temozolomide – Busulfan 2. Platinum Compounds • Cell-cycle phase–non-specific agents – Cisplatin – Carboplatin – Oxaliplatin 3. Antimetabolites • Folic acid analogs: – Methotrexate – Pemetrexed • Pyrimidine analogs: – – – – – Cytarabine Fluorouracil Capecitabine Floxuridine Gemcitabine More Antimetabolites • Purine analogs: – – – – – – – Mercaptopurine Thioguanine Pentostatin Fludarabine Cladribine Nelarabine Clofarabine 4. Hypomethylating Agents • Newer class of anticancer drugs • Become incorporated into the DNA – Azacitidine – Decitabine 5. Antitumor Antibiotics • Cytotoxic drugs originally isolated from cultures of Streptomyces • Used to treat only cancer, not infection • Injure cells through direct interaction with DNA • Poor GI absorption: IV administration • Two main groups: – Anthracyclines – Non-anthracyclines Anthracyclines • • • • • • • Doxorubicin Liposomal Doxorubicin Daunorubicin Epirubicin Idarubicin Valrubicin Mitoxantrone Non-Anthracyclines • Dactinomycin (Actinomycin D) • Bleomycin • Mitomycin 6. Mitotic Inhibitors • Vinca alkaloids: – Vincristine – Vinblastine – Vinorelbine • Taxanes: – Paclitaxel – Docetaxel • Other: – Ixabepilone – Eribulin – Estramustine 7. Topoisomerase Inhibitors • Nuclear enzymes that alter the shape of supercoiled DNA: – – – – Topotecan Irinotecan Etoposide Teniposide 8. Miscellaneous Cytotoxic Drugs • • • • • • • Asparaginase Pegaspargase Hydroxyurea Mitotane Procarbazine Dacarbazine Altretamine Hormonal Agents • Used primarily for breast cancer and prostate cancer • Mimic or block the actions of endogenous hormones Breast Cancer • Most common cancer affecting women in the United States • Principal treatments: – – – – Surgery Radiation Cytotoxic drugs Hormonal drugs Hormonal Agents Two major groups for breast cancer: • Anti-estrogens – (e.g., tamoxifen) • Aromatase inhibitors – (e.g., anastrozole) Adjuvant treatments: • • • • Trastuzumab Ado-trastuzumab emtansine Pertuzumab Lapatinib Tamoxifen • Used for established disease and for decreasing occurrence in high-risk patients • Adjuvant therapy after surgery • Treatment of metastatic disease • Blocks and activates receptors in certain tissues Tamoxifen • Adverse effects: – – – – – – – Hot flashes Fluid retention Vaginal discharge Nausea and vomiting Menstrual irregularities Endometrial cancer Teratogenic • Contraindication: – History of deep vein thrombosis (DVT) Aromatase Inhibitors • Used to treat ER-positive breast cancer in postmenopausal women: – Anastrozole – Letrozole – Exemestane Monoclonal Antibodies to treat Breast Cancer • Trastuzumab • Ado-trastuzumab emtansine Cytotoxic Drugs and Breast Cancer • Used before or after breast surgery • Doxorubicin – an anthracycline-type anticancer antibiotic • Plus cyclophosphamide – an alkylating agent • Followed by paclitaxel – a mitotic inhibitor Preserving Bone Integrity • Bisphosphonates: zoledronate (Zometa) pamidronate (Aredia) • Denosumab (Xgeva) Prostate Cancer • Most common cause of cancer among men in United States • Standard treatment of advanced prostate cancer • Androgen deprivation: – Slows disease progression and increases comfort – Lower testosterone production – Block testosterone receptors with drugs Gonadotropin-Releasing Hormone Agonists • Gn-RH • Suppress production of androgens by the testes • Gn-RH drugs for prostate cancer – – – – Leuprolide Triptorelin Goserelin Histrelin • Co-treatment with an androgen receptor blocker Gonadotropin-Releasing Hormone Agonists • Adverse effects – Generally well tolerated – Hot flashes – Testosterone loss may aggravate bone pain and urinary obstruction • Concurrent treatment with androgen receptor blocker can minimize these effects GnRH Antagonists • Suppress production of androgens • Do not produce initial tumor flair – Abarelix – Degarelix Androgen Receptor Blockers • Also known as anti-androgens • Indicated for advanced androgen-sensitive prostate cancer with castration: – Flutamide – Bicalutamide – Nilutamide Abiraterone • CYP17 Inhibitor • Combined use with prednisone to treat metastatic castration-resistant prostate cancer (previously treated with docetaxel) • Adverse effects: – – – – hypokalemia joint swelling muscle discomfort hepatotoxicity Other Drugs for Prostate Cancer • Sipuleucel-T • Ketoconazole • Cytotoxic anticancer drugs: – Docetaxel – Cabazitaxel – Estramustine EGFR-Tyrosine Kinase Inhibitors • • • • • • Cetuximab Gefitinib Erlotinib Panitumumab Aftinib Lapatinib BCR-ABL Tyrosine Kinase Inhibitors • Preferred drugs for chronic myeloid leukemia (CML) • Imatinib – Considered the model of a successful targeted anticancer drug – Highly effective – Well tolerated • • • • • Atinib Nilotinib Bosutinib Pontanib Nilotinib Multi-Tyrosine Kinase Inhibitors • • • • • • • Sorafenib Sunitinib Axitinib Pazopanib Vandetanib Cabozantinib Regorafenib mTOR Kinase Inhibitors • Temsirolimus – Indicated for IV therapy of advanced renal cell carcinoma • Everolimus ▪ (1) advanced renal cell carcinoma after failure with sorafenib or sunitinib ▪ (2) subependymal giant cell astrocytoma (SEGA) in patients who are not candidates for curative surgical resection ▪ (3) progressive neuroendocrine tumors of pancreatic origin Targeted Drugs • Designed to bind with specific molecules that drive tumor growth • Many are antibodies that bind with specific antigens on tumor cells – Brentuximab vedotin, an antibody-drug conjugate CD20-Directed Antibodies • Rituximab • Ofatumumab • Ibritumomab tiuxetan linked with yttrium-90 • Tositumomab and 131I-tositumomab (iodine-131) Angiogenesis Inhibitors • Suppress formation of new blood vessels • Deprive solid tumors of blood supply needed for growth • Bevacizumab – Only one approved for treating cancer Bevacizumab • Metastatic colorectal cancer • Can delay tumor progression and prolong life • Adverse effects: – – – – – – GI perforation hemorrhage disruption of wound healing nephrotic syndrome hypertensive crisis thromboembolism Proteasome Inhibitors • Intracellular multi-enzyme complexes that degrade proteins • Bortezomib – (1) multiple myeloma, both as first-line therapy and for patients who have not responded adequately to other therapies – (2) mantle cell lymphoma in patients with at least 1 prior year of therapy • Adverse effects: – Weakness, nausea, diarrhea, thrombocytopenia, anemia, neutropenia, constipation, anorexia Histone Deacetylase Inhibitors • Vorinostat • Romidepsin 54 Other Drugs • Ipilimumab (Yervoy), approved in 2011 – Indicated for unresectable or metastatic melanoma Biologic Response Modifiers: Immunostimulants • Drugs that alter host responses to cancer • Enhance immune attack against cancer cells • Interferon alfa-2a and interferon alfa-2b • Aldesleukin (interleukin-2) • Bacillus Calmette and Guerin (BCG) vaccine Glucocorticoids • High doses required for cancer patients • Used in combination with other agents to treat lymphoid tissue cancers (directly toxic) • Acute and chronic lymphocytic leukemia, Hodgkin’s disease, non-Hodgkin’s lymphomas, and multiple myeloma • Multiple serious side effects with high doses More Glucocorticoids • Also used to manage complications of cancer and cancer therapy • Suppression of chemotherapy-induced nausea and vomiting • Reduction in cerebral edema • Reduction in pain • Suppression of hypercalcemia in steroid-responsive tumors • Can improve appetite and promote weight gain Thalidomide • Causes severe birth defects • Two approved indications: – (1) multiple myeloma, an incurable cancer of the bone marrow – (2) erythema nodosum leprosum (ENL), a painful complication of leprosy. Other Non-cytotoxic Anticancer Drugs • • • • • • • • Retinoids Alitretinoin Bexarotene Tretinoin Arsenic trioxide Denileukin diftitox Lenalidomide Progestins QUESTIONS?
