FoM_Week_6_Study_Guide_-_FA_2023.pdf

Drug Mechanism Effect Use Side Effects Folic acid analog, inhibits dihydrofolate reductase ↓ synthesis of dTMP (DNA) ↓ RNA ↓ Protein (↓ Met) Myelosuppression Hepatotoxic Nephrotoxic Folate deficiency Purine analog, induce mutations because can pair with both cytosine and thymine and inhibit...

Drug Mechanism Effect Use Side Effects Folic acid analog, inhibits dihydrofolate reductase ↓ synthesis of dTMP (DNA) ↓ RNA ↓ Protein (↓ Met) Myelosuppression Hepatotoxic Nephrotoxic Folate deficiency Purine analog, induce mutations because can pair with both cytosine and thymine and inhibit de novo purine synthesis. ↓ purine synthesis ↑ apoptosis Head, Neck, Breast, Lung, Sarcomas, Leukemias, Lymphomas Acute Leukemia, CML prevent organ rejection. SLE (Lupus) Rheumatoid arthritis 5-FdUMP binds thymidylate synthase ↓ dTMP Solid tumors: Lung, breast, ovary, prostate, cervix, bladder, head and neck, GI adenocarcinoma (i.e., colon, pancreas) Basal cell (topical) (FA) Myelosuppression Hand-foot syndrome (FA) Chain termination (FA) Inhibits DNA, RNA polymerases Chain termination (FA) Inhibits DNA, RNA polymerases Leukemias (FA) Lymphomas (FA) Myelosuppression, Cerebellar cytotoxicity, Pancytopenia (FA) Inhibits DNA replication, increases apoptosis Solid tumors (FA) Testicular CA (FA) Small cell lung (FA) Leukemias (FA) Lymphomas (FA) Myelosuppression Alopecia Cell Cycle Specific Drugs Antimetabolites Methotrexate Azathioprine 6-Mercaptopurine 6-Thioguanine Myelosuppression ↑risk of toxicity with allopurinol (FA) Activated by HPRT 5-Fluorouracil (5FU) Azthioprine metab. to 6-Mercaptopurine Pyrimidine analog, specifically uracil Inhibits Thymidylate synthase. Cytarabine (ara-C) Pyrimidine analog, specifically, cytosine Gemcitabine Pyrimidine analog, specifically, cytosine Topoisomerase II Inhibitors Etoposide Teniposide Inhibit Topoisomerase II and thereby induce double-strand DNA breaks. 1 Microtubule Inhibitors Vincristine Vinblastine Vinca alkaloids Bind β-tubulin Prevent formation of mitotic spindle (microtubules) Cause metaphase arrest Paclitaxel (a taxane/taxoid) Stabilize microtubules of mitotic spindle Cell cycle Independent (FA) Note: Dr. Janknecht used the term nonspecific instead of independent Alkylating Agents Busulfan Cyclophosphamide Prevent progression to anaphase (FA) Addition of alkyl group Cross-links DNA Addition of alkyl group Cross-links DNA at Guanine residues, Activated in Liver Also, effects on RNA and protein Nitroureas Carmustine Lomustine Procarbazine Anti-Tumor Antibiotics Bleomycin Addition of alkyl group Addition of alkyl group Free radical formation Intercalates into DNA Vincristine – neurotoxicity (FA) Peripheral neuropathy Bone marrow ablation prior to transplant Solid tumors (FA) Prostate, lung, breast, ovarian Leukemias (FA) Lymphomas (FA) Rheumatic disease (SLE, etc.) (FA) Myelosuppression Pulmonary fibrosis Hypopigmentation Myelosuppression (FA) SIADH (FA) Fanconi syndrome (FA) Hemorrhagic cystitis Bladder CA (FA) Mutagenic, teratogenic, carcinogenic (see bladder above) Cross-link DNA Cross blood brain barrier Cross-link DNA Brain CA (Glioblastoma multiforme) DNA strand breaks Hodgkin lymphoma Testicular CA Prevents RNA synthesis (transcription) Wilm’s tumor (renal) (FA) Ewing sarcoma (FA) Rhabdosarcoma Childhood tumors Chelates metals using O2 Dactinomycin (actinomycin D) Solid tumors (Breast, Cervix, Lung, ovary, testis, bladder) Leukemias Lymphomas Hodgkin’s Kaposi’s sarcoma Breast cancer Ovarian cancer 2 Vinblastine – bone marrow suppression (FA) Myelosuppression Neuropathy Hypersensitivity Pulmonary fibrosis Hyperpigmentation (FA) Some Myelosuppression (FA) Myelosuppression Anthracyclines Doxorubicin Daunorubicin (FA) Topoisomerase I Inhibitors Camptothecins Topotecan Irinotecan Free radical formation (FA) Intercalates into DNA DNA strand breaks, inhibits DNA replication and transcription Solid tumors (FA) Leukemias (FA) Lymphomas (FA) Inhibit Topoisomerase I and thus lead to single strand DNA breaks Inhibit replication. Inhibit transcription Topotecan – Ovarian CA Irinotecan – Colorectal CA Both used to treat metastatic disease Platinum Compounds Cisplatin Cross-link DNA Carboplatin Cross-link DNA Testicular CA Bladder CA Ovarian CA GI CA Lung CA Sarcoma Neuroblastoma Testicular CA Bladder CA Ovarian CA GI CAs Lung CA Oxaliplatin Cross-link DNA Colorectal cancer SERM (selective estrogen receptor modulator). blocks binding of estrogen to its receptor Estrogen receptor antagonist in breast (but also partial agonist in some other organs) Post-menopausal breast cancer SERM Estrogen receptor mixed agonist (bone)/antagonist (breast) Osteoporosis Preventative for high patients with high risk of breast cancer development Cardiotoxicity Myelosuppression Alopecia Ototoxicity Nephrotoxicity Peripheral neuropathy Ototoxicity Nephrotoxicity Peripheral neuropathy Reduced side effects compared to cisplatin Nuclear Hormone Receptors as Targets Sex Hormone Receptor Inhibitors Tamoxifen Raloxifene 3 Partial agonist in endometrium: ↑risk of endometrial cancer (FA) Amenorrhea Vaginal bleeding/discharge ↑ risk DVT, PE (FA) Hot flashes ↑ risk DVT, PE Hot flashes Enzalutamide Blocks binding of androgens to their cognate receptor Androgen receptor antagonist Prostate carcinoma Inhibits aromatase Prevents conversion of testosterone → estradiol Advanced Breast Cancer Down regulates estrogen receptor Estrogen receptor degradation Tamoxifenresistant breast cancer Drugs Targeting Androgen Pathway Abiraterone Inhibits CYP17A1 Inhibits androgen (testosterone) synthesis Castrationresistant prostate cancer Retinoic Acid Receptor Agonist ATRA (all-trans retinoic acid) Agonist of retinoic acid receptor Stimulates retinoic acid receptor (and the PML-RAR fusion in APL) Acute Promyelocytic Leukemia (APL). Acne vulgaris, keratosis pilaris teratogenic Inhibits ABL/BCRABL, KIT, PDGFR CML Ph+ ALL Fluid retention (FA) HER2-positive breast cancer Cardiac dysfunction (5%) Cardiotoxicity Aromatase Inhibitors Letrozole Drugs Targeting Estrogen Receptor Fulvestrant Novel Targeted Therapies: Pharm II Lecture Receptor Tyrosine Kinase Inhibitors Imatinib Fatigue Musculoskeletal pain Peripheral edema Hot Flashes Including Biologics Kinase inhibitor Trastuzumab Anti-HER2 monoclonal antibody Lapatinib Kinase inhibitor Inhibits HER2, EGFR Ado-trastuzumab Emtansine Monoclonal attached to toxic molecule Erlotinib Kinase inhibitor Toxin inhibits spindle assembly in HER2-positive cancer cells EGF receptor Dil.cardiomyopathy Gefitinib 4 HER2-positive breast cancer HER2-positive breast cancer Lung CA – Advanced NSCLC Rash (FA) Diarrhea (FA) Cetuximab Monoclonal antibody Prevents EGF binding the receptor Sequesters VEGF and thus prevents binding to its receptor Lung CA – SCC Colon CA Bevacizumab Monoclonal antibody against VEGF: angiogenesis inhibitor Inhibits serine/threonine kinase activity Inhibits mutant BRaf (V600E mutant) Late-stage melanoma Inhibition of DNA methyltransferases Reactivation of tumor suppressor genes by causing the demethylation of DNA regulatory elements Reactivation of tumor suppressor genes by causing the demethylation of DNA regulatory elements Myelodysplastic syndrome (“preleukemia”) Cytokine that can stimulate immune response Attacking cancer cells Ipilimumab Monoclonal antibody that blocks CTLA-4 Pembrolizumab Monoclonal antibody that blocks PD-1 Promotes initial activation of antitumor T cells Prevents tumormediated inactivation of T cells Metastatic renal cell carcinoma Metastatic malignant melanoma Late-stage melanoma B-RAF Inhibitors Vemurafenib Dabrafenib Epigenetic Targets 5-Azacytidine 5-Aza-2’deoxycytidine Immunotherapy Interleukin-2 (IL-2) Inhibition of DNA methyltransferases 5 Metastatic colorectal CA Lung CA - NSCLC Rash (FA) Diarrhea (FA) Elevated LFT’s (FA) Hemorrhage (FA) Blood clots (FA) ↓ wound healing Myelodysplastic syndrome (“preleukemia”) Solid tumors with mismatch repair deficiency (including advanced melanoma) Capillary leaks