Drug Summary Table: Chapter 37 Pharmacology of Cancer: Genome Synthesis, Stability, and Maintenance

Serious and Common Drug Clinical Applications Adverse Effects Contraindications INHIBITORS OF THYMIDYLATE SYNTHASE Mechanism Inhibit thymidylate synthase, thereby decreasing cellular availability of dTMP and causing Fluorouracil (5-FU) Breast cancer Coronary atherosclerosis, Severe bone marrow thrombophlebitis, Gastrointestinal cancers depression gastrointestinal ulcer, Skin cancer (topical application) Poor nutritional state myelosuppression, cerebellar Serious infection syndrome, visual changes, Dihydropyrimidine stenosis of lacrimal system dehydrogenase Alopecia, rash, pruritus, deficienc y photosensitivity, Pregnanc y gastrointestinal disturbance, stomatitis, headache Capecitabine Metastatic colorectal cancer Breast cancer Same as fluorouracil Dihydropyrimidine dehydrogenase deficienc y Severe renal impairment Myelosuppression, angina, Hypersensitivity to myocardial infarction, stroke, pemetrexed thrombophlebitis, liver Severe renal damage, bullous skin rash impairment Fatigue, nausea, vomiting, diarrhea, stomatitis Therapeutic Considerations thymineless cell death 5-FU is a uracil analogue that, after intracellular modification, inhibits thymidylate s ynthase by binding to the deox yuridylate (substrate) site on the enzyme In addition to inhibiting thymidylate synthase, 5-FU interferes with protein synthesis after the drug meta-bolite FUTP is incorporated into mRNA Folinic acid can be used to potentiate the action of 5-FU Orally available prodrug form of 5 -FU

Pemetrexed

Nonsmall cell lung cancer Malignant pleural mesothelioma (in combination with cisplatin)

Pemetrexed is a folate analogue that, after intracellular modification, inhibits thymidylate s ynthase by binding to the methylenetetrahydrofolate (cofactor) site on the enzym e Coadministered with folic acid and vitamin B12 to reduce hematologic and gastrointestinal toxici ty

INHIBITORS OF PURINE METABOLISM Mechanism Drug metabolites inhibit IMPDH and other synthetic enzymes, thereby interfering with AMP and GMP synthesis 6-Mercaptopurine Acute lym phoid leukemia, acute Pancreatitis, Pregnanc y Effectiveness and toxicity increased (6-MP) m yeloid leukemia, Crohn's disease myelosuppression, by allopurinol Azathioprine hepatotoxicity, infection (6-MP) Azathioprine is a less toxic prodrug of Immunosuppression in renal Gastritis 6-MP transplantation, rheumatoid Azathioprine is used for arthritis, inflammatory bowel immunosuppression of autoimmune disease (azathioprine) diseases Pentostatin Cardiac arrhythmia, heart Hair y cell leukemia Hypersensitivity to Selective inhibitor of adenosine failure, myelosuppression, T-cell lym phoma pentostatin deaminase (ADA) hepatotoxicity, neurotoxicity, nephrotoxicity, pulmonary toxicity Rash, shaking chills,

vomiting, m yalgia, upper respiratory infection, fever INHIBITORS OF RIBONUCLEOTIDE REDUCTASE Mechanism Inhibit ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides Hydroxyurea Myelosuppression, secondary Severe bone marrow Reduces tyrosine free radical critical Hematologic malignancies leukemia with long-term use depression Head and neck cancers to mechanism of action of Melanoma Gastrointestinal toxicity, skin ribonucleotide reductase Ovarian carcinoma ulcer In sickle cell anemia, hydrox yurea is Sickle cell anemia (adults only) thought to act by increasing hemoglobin F PURINE AND PYRIMIDINE ANALOGUES THAT ARE INCORPORATED INTO DNA Mechanism Incorporation into DNA and RNA results in inhibition of DNA polymerase, thereby causing cell death Thioguanine Myelosuppression, Acute m yeloc ytic leukemia Prior resistance to Guanine analogue hyperuricemia, intestinal thioguanine or perforation, hepatotoxicity, mercaptopurine infection Gastrointestinal disturbance Fludarabine Aplasia of skin, autoimmune Hypersensitivity to B-cell chronic lymphoc ytic Purine nucleotide analogue phosphate hemolytic anemia, leukemia fludarabine myelosuppression, Non-Hodgkin's lym phoma neurotoxicity, pneumonia, infection Edema, gastrointestinal disturbance, asthenia, fatigue Cladribine Febrile neutropenia, Hair y cell leukemia Hypersensitivity to Purine analogue myelosuppression, Multiple sclerosis cladribine neurotoxicity, infection Rash, injection site reaction, nausea, headache Cytarabine (araC) Acute lym phoid leukemia Myelosuppression, Hypersensitivity to Cytidine analogue neuropathy, nephrotoxicity, Acute m yeloid leukemia cytarabine liver dysfunction, infection Chronic m yeloid leukemia Meningeal leukemia Thrombophlebitis, rash, Hodgkin's disease hyperuricemia, Non-Hodgkin's lym phoma gastrointestinal disturbance, ulcers of mouth or anus Azacytidine Myelosuppression, renal Myelodysplastic s yndrome Advanced malignant Cytidine analogue failure hepatic tumors Peripheral edema, gastrointestinal disturbance, hepatic coma, lethargy, cough, fever Gemcitabine Myelosuppression, febrile Pancreatic cancer Hypersensitivity to Cytidine analogue neutropenia, pulmonary Nonsmall cell lung cancer gemcitabine

toxicity, hepatoxicity, hemolytic uremic syndrome Fever, gastrointesinal disturbance, liver enzyme elevation, edema, rash, paresthesias AGENTS THAT DIRECTLY MODIFY DNA STRUCTURE: ALKYLATING AGENTS Mechanism Covalently bind DNA, often crosslink to DNA or associated proteins Cyclophosphamide Autoimmune diseases Myelosuppression, cardiomyopathy, Stevens Leukemias and lymphomas Johnson syndrome, Advanced m ycosis fungoides hemorrhagic cystitis, Neuroblastoma azoospermia, interstitial Ovarian cancer pneumonia, infection Retinoblastoma Breast cancer Alopecia, gastrointestinal Malignant histioc ytosis disturbance, leukopenia, amenorrhea Mechlorethamine Leukemia and Hodgkin's disease Same as cyclophosphamide Melphalan (mechlorethamine) Estramustine Lymphoma (melphalan) Chlorambucil Prostate cancer (estramustine) Mitomycin Leukemia (chlorambucil) Thiotepa Gastric and pancreatic cancer Carmustine (mitom ycin) Dacarbazine Bladder cancer (thiotepa) Procarbazine Brain cancer (carmustine) Altretamine Hodgkin's disease (dacarbazine) Hodgkin's disease (procarbazine) Ovarian cancer (altretamine) Breast cancer Ovarian cancer Bladder cancer Sarcoma Hodgkin's disease

Pregnanc y

Severely depressed bone marrow function

Acrolein, a metabolite of cyclophosphamide, causes hemorrhagic c ystitis; this adverse effect can be prevented by coadministration with mesna

Presence of known Thiotepa is instilled directly in the infectious disease bladder (mechlorethamine) Carmustine is a nitrosurea that Active attaches a carbamoyl group to target thrombophlebitis or proteins thromboembolic disorder (estramustine) Coagulation disorder or renal impairment (mitom ycin) Hepatic, renal or bone marrow dysfunction (thiotepa) Severe bone marrow depression (procarbazine, altretamine) Severe neurologic toxicity (altretamine) AGENTS THAT DIRECTLY MODIFY DNA STRUCTURE: PLATINUM COMPOUNDS Mechanism Crosslink intrastrand guanine bases Cisplatin Nephrotoxicity (cisplatin), Genitourinar y cancers Severe bone marrow Cisplatin can be injected Carboplatin myelosuppression, peripheral depression Lung cancers intraperitoneally for treatment of neuropathy, ototoxicity Renal or hearing ovarian cancer Electrolyte imbalance impairment Coadministration of amifostine with cisplatin can limit nephrotoxicity Oxaliplatin Acute and persistent Colorectal cancer Hypersensitivity to Acute neurotoxicity is exacerbated by

neurotoxicity, oxaliplatin myelosuppression, colitis, hepatic dysfunction Gastrointestinal disturbance, back pain, cough, fever AGENTS THAT DIRECTLY MODIFY DNA STRUCTURE: BLEOMYCIN Mechanism Binds oxygen and chelates Fe(II); binds DNA and leads to strand breaks via generation of Bleomycin Pulmonary fibrosis, vascular Hypersensitivity to Testicular cancer disease, myocardial Hodgkin's disease bleom ycin infarction, stroke, Raynaud's, Non-Hodgkin's lym phoma hepatotoxicity, nephrotoxicity, Squamous cell carcinoma rare myelosuppression Alopecia, rash, hyperpigmentation, skin tenderness, gastrointestinal disturbance, stomatitis TOPOISOMERASE INHIBITORS Mechanism Inhibit topoisomerase I or topoisomerase II, leading to DNA strand breakage Irinotecan Life-threatening diarrhea, Colorectal cancer (irinotecan) Severe bone marrow Topotecan myelosuppression, f ebrile Small cell lung cancer, cervical depression neutropenia, liver dysfunction, carcinoma, ovarian cancer interstitial lung disease (topotecan) Alopecia, eosinophilia Doxorubicin Heart failure (especially Leukemias, lymphomas, breast Pre-existing heart Daunorubicin doxorubicin), cancer, bladder cancer, thyroid failure Epirubicin myelosuppression cancer, GI cancer, Severe bone marrow nephroblastoma, osteosarcoma, Alopecia, rash, depression ovarian cancer, small cell gastrointestinal disturbance Severe hepatic carcinoma of lung, soft tissue dysfunction sarcoma (doxorubicin) (epirubicin) Acute lym phoid leukemia and acute m yeloid leukemia (daunorubicin) Breast cancer (epirubicin) Etoposide Testicular and lung cancer, Same as doxorubicin Hypersensitivity to Teniposide leukemia (etoposide) etoposide or Acute lym phoid leukemia, nonteniposide Hodgkin's lymphoma (teniposide) Amsacrine Recurrent leukemia Ovarian cancer ECG changes including QT prolongation, paralytic ileus, myelosuppression, convulsion, azoospermia, hepatotoxicity Hypersensitivity to amsacrine

exposure to cold temperatures

oxidative intermediates Effects on pulmonary function are dose-limiting and irreversible

Irinotecan and topotecan are camptothecins that inhibit topoisomerase I Action is specific to S phase Doxorubicin, daunorubicin, an d epirubicin are anthrac yclines that inhibit topoisomerase II Excreted in bile (reduce dose in patients with hepatic dysfunction) Action is specific to G2 phase

Etoposide and teniposide are epipodophyllotoxins that inhibit topoisomerase II Action is specific to late S and G2 phases Inhibits topoisomerase II

Alopecia, gastrointestinal disturbance AGENTS THAT INHIBIT MICROTUBULE POLYMERIZATION Mechanism Bind tubulin subunits and prevent microtubule polymerization Vinblastine Myelosuppression, Metastatic testicular cancer Bacterial infection Bone marrow suppression is dosehypertension, neurotoxicity, Lymphoma Significant limiting azoospermia AIDS-related Kaposi's sarcoma granuloc ytopenia Breast cancer Alopecia, bone pain, Choriocarcinoma gastrointestinal disturbance Malignant histioc ytosis Mycosis fungoides Vincristine Peripheral neuropathy, Leukemias Charcot-Marie-Tooth Peripheral neuropathy is dose-limiting myopathy, myelosuppression syndrome Hodgkin's disease Non-Hodgkin's lym phoma Alopecia, gastrointestinal Intrathecal use Rhabdom yosarcoma disturbance, diplopia Nephroblastoma AGENTS THAT INHIBIT MICROTUBULE DEPOLYMERIZATION Mechanism Bind polymerized tubulin and inhibit microtubule depolymerization Paclitaxel Myelosuppression, pulmonary Severe neutropenia Ovarian cancer Peripheral neuropathy is dose-limiting Albumin-bound toxicity, severe Breast cancer paclitaxel hypersensitivity reaction, Nonsmall cell lung cancer myopathy, peripheral AIDS-related Kaposi's sarcoma neuropathy Alopecia, gastrointestinal disturbance, arthralgia Docetaxel Myelosuppression, Stevens - Severe neutropenia Breast cancer Myelosuppression is dose-limiting Johnson syndrome, fluid Gastric cancer retention syndrome leading to Prostate cancer severe edema, neuropathy, Nonsmall cell lung cancer hepatotoxicity, colitis Alopecia, gastrointestinal disturbance, asthenia, fever ANTINEOPLASTIC DIHYDROFOLATE REDUCTASE INHIBITOR Mechanism Folate analogue that competitively inhibits mammalian DHFR and thereby prevents the regeneration of tetrahydrofolate from dihydrofolate Methotrexate Many tumor types, Myelosuppression, liver failure, Pregnanc y The use of high-dose gastrointestinal hemorrhage, including carcinomas of Breastfeeding methotrexate in cancer the breast, lung, head and mucous membrane Patients with psoriasis/rheumatoid chemotherapy has been inflammation, hepatic cirrhosis, neck; acute lymphoblastic arthritis who also have alcoholism, broadened by the application of kidney disease, interstitial leukemia; alcoholic liver disease, chronic liver folinic acid rescue pulmonary disease, choriocarcinoma disease, preexisting blood Methotrexate toxicity to the hyperuricemia Autoimmune diseases dyscrasia, or laboratory evidence of gastrointestinal mucosa and including psoriasis, Gastrointestinal disturbance, immunodeficienc y s yndrome bone marrow is generally rheumatoid arthritis stomatitis, alopecia, reversible after therapy is

Early stage ectopic pregnancy

photosensitivity, rash

discontinued Extremely toxic to the fetus because folic acid is essential for differentiation of fetal cells and for neural tube closure Under investigation as an abortion-inducing agent, either alone or in combination with the prostaglandin analogue misoprostol Avoid coadministration of polio vaccine in immunosuppressed patients receiving methotrexate as a component of chemotherapy Avoid concurrent alcohol intake Use extreme caution with coadministration of naproxen and phenylbutazone due to sporadic case reports of deaths Coadministration with trimethoprim may result in severe methotrexate toxicity Oral absorption of methotrexate can be decreased by up to 50% in patients receiving oral antibiotic mixtures containing paromom ycin, neom ycin, nystatin, and vancom ycin