Katzung Review Cancer

CHEMOTHERAPEUTIC DRUGS CANCER CHEMOTHERAPY

Cytarabine (IV) - inhibit DNA polymerase

Alkylating Agents Cell Cycle Nonspecific Alkylate nucleophilic groups on DNA bases (N7 guanine) Crosslinking, abnormal base pairing, DNA strand breakage Cyclophosphamide - Hepatic biotransformation needed - Non Hodgkin’s lymphoma, breast/ovarian CA, neuroblastoma - Hemorrhagic cystitis (acrolein) – hydrate, give mesna to reduce incidence Mechlorthamine - Hodgkin’s disease - Toxcicity: vesicant actions Cisplatin/Carboplatin - Testicular CA (bladder, lung, ovary CA) - Neurotoxic (peripheral neuritis, acoustic nerve damage) and nephrotoxic - Carboplatin less nephrotoxic, greater myelosuppresant action - rescue drug: Amifostine Procarbazine - forms H2O2, DNA strand scission - component for Hodgkin’s - myelosuppresant, GI irritation - MAO inhibition, disulfirma like reaction, leukemogenic Busulfan - CML - Cause adrenal insufficiency, pulmonary fibrosis, skin pigmentation Carmustine (BCNU) - Highly lipid soluble and Lomustine - Adjuncts in the management of brain tumors (CCNU)

- of all the antimetabolites, is the most specific for the S phase - treatment for acute leukemias

Toxicity: GI irritation and myelosuppression neurotoxicity at high dose (cerebellar dysfunction and peripheral neuritis) Fluorouracil (5-FU) - inhibits thymidylate synthase

- “thymineless death of cells” - Bladder, breast, colon, head and neck, liver, ovarian CA - Topically for keratoses and superficial BCC

Toxcity: GI distress, myelosuppression, alopecia Plant Alkaloids Cell cycle specific Vinblastine/ Vincristine (IV) - Block formation of mitotic spindle (prevent microtubule assembly) - Act primarily on M phase

- Vincristine: Acute leukemias, lymphomas, Wilm’s tumor, choriocarcinoma - Vinblastine: GI distress, alopecia, bone marrow suppression

Toxicity: Vincristine: neurotoxic actions (areflexia, peripheral neuritis, paralytic ileus) Vinblastine: GI distress, alopecia, bone marrow suppression

Antimetabolites -structurally similar to endogenous compounds -cell cycle specific – primarily on phase S -cytotoxic, immunosuppresant Folic acid antagonist - Methotrexate Purine - Mercaptopurine, thioguanine Pyrimidine - Fluorouracil, Cytarabine

Etoposide and Teniposide - Interact with topoisomerase II, - Lung (small cell), prostate, degrade DNA testicular CA - Inhibits electron transport - Most active in late S and early G2 Toxicity: GI irritant, alopecia, myelosuppression

Methotrexate - Inhibit dihydrofolate reductase - Decrease thymidylate, purine and AA synthesis

Paclitaxel and Docetaxel (IV) - Interfere with mitotic spindle - Advanced breast and - Prevent microtubule disassembly ovarian CA Toxicity: neutropenia, thrombocytopenia, high incidence of peripheral neuropathy, hypersensitivity reactions Docetaxel: neurotoxicity and bone marrow depression

- Does not penetrate CNS - Clearance dependent on renal function - Choriocarcinoma, acute leukemias, non Hodgkin’s/cutaenous T cell lymphomas, breast CA - Also used in rheumatoid arthritis and ectopic pregnancy - abortifacient

Toxicity: myelosuppression mucositis folinic acid (leucovorin) reduces toxic action on normal cells “leucovorin rescue” long term: hepatotoxicity and pulmonary infiltrates/fibrosis Mercaptopurine (6-MP) and Thioguanine (6-TG) - activated by HGPRTase and - allopurinol inhibit 6-MP metabolism inhibit enzymes in purine (toxic levels may be reached rapidly) metabolism - acute leukemias, CML Toxicity: dose limiting myelosuppression hepatic dysfunction

Antibiotics Doxorubicin and Danorubicin (IV) - Intercalate between base pairs - Inhibit topoisomerase II - Generate free radicals - Block RNA/DNA synthesis - Cause DNA strand scission

- Cell cycle NON specific - Doxorubicin: Hodgkin’s, myelomas, sarcomas, breast, endometrial, lung, ovarian, thyroid - Daunorubicin: mainly for acute leukemias - Idarubicin: AML

Toxicity Bone marrow suppression, GI distress, severe alopecia Cardiotoxicity – protective effect by Dexrazoxane Rescue drug Dacrazone Bleomycin (IV) Generates free radicals Bind to DNA, cause strand

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Hodgkin’s disease, testicular CA

breaks - Lymphomas, SCC Inhibit DNA synthesis Cell Cycle specific: G2 phase Toxicity: Pulmonary dysfunction (pneumonitis, fibrosis)- dose limiting Hypersensitivity, mucocutaneous reactions Dactinomycin (IV) Binds to dsDNA - Cell cycle NON specific Inhibits DNA dependent RNA - Excreted in bile synthesis - Melanoma, Wilm’s tumor - Toxicity: myelosuppression, skin reaction, GI irritation Mitomycin (IV) Metabolized by liver enzymes to form alkylating agent DNA crosslinking

- Cell cycle NON Specific - Acts against hypoxic tumor cells - Combination regimen for cervix, stomach, pancreas, lung adenocarcinoma

- Toxicity: severe myelosuppression - Toxic to heart, liver, lung, kidney Hormonal Anticancer Agents Glucocorticoids - Prednisone: most commonly used glucocorticoid in cancer chemotherapy - Leukemias/lymphomas Sex hormone antagonists Tamoxifen - selective estrogen receptor modulator -used in receptor positive breast CA -preventive effect for women with high risk of breast CA - activity in progesterone resistant endometrial CA - Toxicity: N/V, hot flushes, vaginal bleeding, venous thrombosis Toremifene - Newer, used in advanced breast CA Flutamide - Androgen receptor antagonist - Prostatic CA - ToxicitY: gynecomastia, hot flush, hepatic dysfunction Gonadotropin Releasing Hormone Analogs Leuprolide, - GnRH agonists Goserelin, - Effective in prostatic CA Nafarelin - Inhibit LH and FSH - Leuprolide adverse effects:bone pain, gynecomastia, hematuria, impotence, testicular atrophy Aromatase Inhibitors Anastrozole, - Inhibit aromatase (convert androgen to estrogen) Letrozole - Advanced breast CA, unresponsive to Tamoxifen - Toxicity: N/D, hot flush, bone/back pain, dyspnea Miscellaneous Anticancer Agents - Depletes serum asparagines Asparaginase - T cell auxotrophic cancers (leukemias, lymphomas) (IV) - Hypersensitivities, acute pancreatitis, bleeding Imatinib - Inhibits tyrosine kinase of Bcr-Abl, ckit - Effective in CML, GIST - Toxicity: diarrhea, myalgia, fluid retention Interferons - Alpha interferons: hairy cell leukemia, early CML, T cell lymphomas - Toxicity: myelosuppression and neurologic dysfunction

Monoclonal antibodies

- Rituximab: non Hodgkin’s, low grade lymphomas (hypersensitivity and myelosuppression) - Trastuzumab: breast CA with Her2 Neu overexpression (cardiotoxicity)

CHEMOTHERAPEUTIC DRUGS IMMUNOPHARMACOLOGY Immunosuppressive Agents Corticosteroids (glucocorticoids)

Cyclosporine -bind to cyclophilin - erratic bioavailability - effective in other immune diseases - Cyclosporine : renal dysfunction, neurotoxicity (paresthesias 50%) Tacrolimus and Sirolimus -bind to FKBP - Sirolimus: no effect on cytokine production

Mycophenolate Mofetil -converted to mycophenolic acid -inhibits IMD, de novo purne pathway -suppress both B/T Azathioprine - Transformed to mercaptopurine -inhibit enzymes in purine metabolism - Cytotoxic in early phase of lymphoid proliferation Cyclophosphamide -transformed to an alkylating agent, cytotoxic

- Toxicity: adrenal suppression, growth inhibition, muscle wasting, osteoporosis, salt retention, diabetogenesis - Bind to immunophilin, inhibit calcinuerin - interfere with T cell function - Cyclosporine solid organ transplant, GVHD in marrow transplant -Tacrolimus: liver and kidney transplant -Sirolimus: kidney and heart transplant - Toxicity: renal dysfunction, hypertension, neurotoxicity, hyperglycemia, hyperlipidemia, cholelithiasis - Sirolimus: more likely to cause hypertriglyceridemia, hepatotoxicity, diarrhea, myelosuppression - Sole agent in kidney, liver, heart transplant - Toxicity: GI, myelosuppression (neutropenia)

- Greater effect on T cells - Autoimmune diseases, immunosuppresion in renal homografts - Toxicity: myelosuppression, GI - Increased incidence of CA, affected by allopurinol - Greater effect on B cells - Effective in autoimmune diseases, bone marrow transplant - Does not prevent GVH in marrow transplant - Toxicity: hemorrhagic cystitis, pancytopenia, GI, alopecia

Newer Immunosuppresants Etanercept

Leflunomide

Thalidomide

Alefacept

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Recombinant form of TNF receptor Binds TNF-a (decrease IL formation) Rheumatoid arthritis Inhibit dihydroorotic acid dehydrogenase Arrests lymphocytes in G1 phase Rheumatoid arthritis AE: alopecia, rash, diarrhea Sedative drug, teratogenic Suppress TNF production Leprosy, immunologic Wasting syndrome of AIDS patients Targets CD2 receptor on T cell surface, inhibits Tcell activation - For psoriasis - Dose dependent reduction in T cell

Antibodies as Immunosuppressants Antilymphocytic globulin/ - selectively block cellular immunity Antithymocyte globulin - Suppress organ graft rejection - Prevent GVH prior to marrow transplant - Toxicity: hypersensitivity Rho Ig (RhoGAM) - Blocks primary immune response to foreign cells - Prevention of rh hemolytic disease of newborn Monoclonal antibodies Muromonab - Block killing action of cytotoxic T cells Bind to CD3 - Manage renal homograft rejection crisis Daclizumab - Prevent activation of T cells by IL2 Bind to IL2 - Not used for acute rejection - Renal transplants Infliximab - Induces remissions in treatment - Target against TNF alpha resistant Chron’s disease - Effective in IBD Adalimumab - Rheumatoid arthritis - Bind to TNF alpha Monoclonal antibody characteristics MAB MOA Abciximab Gp IIb1/IIIa receptor antagonist Daclizumab Bind to IL2 receptor Infliximab Target TNFa Muromonab Antibody to CD3 Palivizumab Rituximab Trastuzumab

RSV surface protein CD20 antigen binding HER2Neu

Effect Postangioplasty/ACS Renal transplant Chron’s disease, RA acute renal allograft rejection RSV prophylaxis and tx B cell NHL Breast CA

Immunomodulating Agents Aldesleukin - Promote production of cytotoxic T cells - Adjunctive treatment of Renal cell CA and malignant melanoma Interferons - IFN a-2a: hairy cell leukemia, CML, MM, Kaposi’s, hepatitis B and C - IFN B-1b: relapsing Multiple sclerosis BCG - Immunization against TB - Immunostimulant in superficial bladder CA Thymosin - Di George syndrome Mechanisms of Drug Allergy Type I IgE mediated Type II IgM/IgG

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Type III

Complement fixing IgM/IgG

Type IV

Cell mediated

Penicillins and sulfonamides Methyldopa (hemolytic anemia) Hydralazine/Procainamide (SLE) Quinidine (TTP) Agranulocytosis Serum sickness, vasculitis Sulfonamide (Steven Johnson syndrome Topical application of drugs Contact dermatitis