Flashcards in Cancer Chemotherapy Deck (13):
-A monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
-Pembrolizumab is an immune-checkpoint inhibitor.
-It is used to treat metastatic non-small cell lung cancer and advanced melanoma.
-Tox: immune-mediated side effects- inflammation.
-Binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
-CTLA-4 is a negative regulator of T-cell activation.
-The mechanism of action of ipilimumab’s effect in patients with melanoma is through T-cell mediated anti-tumor immune responses.
-Ipilimumab was recently approved for non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer, metastatic hormone-refractory prostate cancer, and melanoma
-Tox: immune-mediated side effects- inflammation of the intestines (colitis), liver (hepatitis), severe skin reaction, nerves, pituitary, adrenal, and thyroid glands.
-MOA-Etoposide forms a ternary complex with topoisomerase II and DNA that cannot dissociate. DNA replication is blocked and double-stranded DNA breaks occur.
-Cells in the S or G2 phases are more sensitive. Resistant cells demonstrate amplification of the mdr-1 gene that encodes the P-glycoprotein drug efflux transporter, mutation or decreased expression of topoisomerase II, or mutations of the p53 tumor suppressor gene, a required component of the apoptotic pathway.
-Etoposide is used in combination with cisplatin in the treatment of small cell carcinoma of the lung due to their lack of cross-resistance.
-The dose-limiting toxicity of etoposide is leukopenia.
-MOA-water replaces the Cl to activate the drug. This creates an alkyator that produces cross-links between adjacent guanines in DNA. The second chloride in cisplatin is replaced by another H2O and the platinum binds to the second adjacent guanine. Cisplatin can also bind to adenine and across strands to a lesser extent. The cisplatin-DNA complex attracts the attention of HMG (high mobility group)-1 and other DNA repair proteins which become irreversibly bound. The resulting distortion to the shape of the DNA prevents effective repair and leads to apoptosis.
-Overexpression of NER components is associated with poor response to cisplatin-based therapy in lung cancer. Resistance to cisplatin and carboplatin, but not oxaliplatin, appears to be partly mediated through loss of function in the mismatch repair (MMR) proteins. MMR proteins, particularly hMLH1, hMLH2, or hMSH6, recognize platinum-DNA adducts and initiate apoptosis.
-Neprotoxicity, otoxicity, Marked nausea and vomiting (use antiemetic loperamide), moderate myelosuppression. (less tox with carboplatin).
-MOA-Hydrolysis of carboplatin removes the bidentate cyclobutanedicarboxylato group; this activation reaction occurs slowly. This creates an alkyator that produces cross-links between adjacent guanines in DNA. The carboplatin-DNA complex attracts the attention of HMG (high mobility group)-1 and other DNA repair proteins which become irreversibly bound. The resulting distortion to the shape of the DNA prevents effective repair and leads to apoptosis.
-Resistance to cisplatin and carboplatin, but not oxaliplatin, appears to be partly mediated through loss of function in the mismatch repair (MMR) proteins. MMR proteins, particularly hMLH1, hMLH2, or hMSH6, recognize platinum-DNA adducts and initiate apoptosis.
-Carboplatin is relatively well tolerated clinically, with less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than that associated with cisplatin. Instead, the dose-limiting toxicity is myelosuppression, primarily evident as thrombocytopenia.
-MOA-It is triphosphorylated and incorporated into DNA where it both inhibits DNA replication by DNA chain termination and induces apoptosis by interference with DNA repair mechanisms. Diphosphorylated gemcitabine also inhibits ribonucleotide reductase to deplete deoxyribonuceotides for DNA synthesis. Therefore, both inhibition of DNA replication in rapidly dividing tumor cells and induction of apoptosis of solid tumor cells at rest are actions of gemcitabine therapy.
-Gemcitabine is inactivated by cytidine deaminase, which is found both in tumor cells and throughout the body.
-Tox: Myelosuppression. Gemcitabine is a very potent radiosensitizer, likely the result of its inhibition of RNR, depletion of dATP, and inhibition of DNA repair and should not be used with radiotherapy.
Irinotecan & Topotecan
-Newer drugs used in the treatment of small cell lung carcinoma are the camptothecins: irinotecan and topotecan.
-Topotecan is listed as a second-line agent for SCLC. Irinotecan is used for advanced colorectal cancer (Phase B and GI)
-MOA-They target topoisomerase I which mediates DNA strand breakage and resealing during DNA replication. More specifically, they inhibit the re-ligation of the broken DNA strand. S-phase specific because DNA replication must be occurring. Irinotecan acts similarly to topotecan but is a prodrug with a bulky piperidino side group that must be cleaved to an active metabolite, SN-38.
-Resistance- lack of carboxylesterase, loss or mutated topo I.
-Topotecan - dose-limiting toxicity is neutropenia, with or without thrombocytopenia. Irinotecan- dose-limiting toxicity with is delayed diarrhea, with or without neutropenia. Polymorphorisms of the liver UGT1A1 enzyme causing decreased glucuronidation of irinotecan causes severe neutropenia and diarrhea. Cholinergic syndrome resulting from the inhibition of acetylcholinesterase activity. .
Paclitaxel & Docetaxel
-MOA-Paclitaxel (Taxol) inhibits mitosis but differently than vincristine or vinorelbine. It binds to the β-tubulin subunit of tubulin and blocks the disassembly of the microtubule bundles to produce aberrant microtubule structures.
-Widely used for ovarian, breast, lung cancer. Docetaxel is more soluble with more predictable blood levels achieved during IV infusion than paclitaxel.
-Resistance is by increased expression of the mdr-1 gene and the P-glycoprotein pump and β-tubulin mutations.
-Toxicity- mainly in bone marrow, neutropenia (G-CSF, filgrastim, used to counteract); peripheral neuropathy. Docetaxel causes less severe peripheral neuropathy and hypersensitivity reactions . Pretreatment with Dexamethasone limits hypersensitivity reactions to both drugs.
Gefitinib & Erlotinib
-MOA-orally active, reversible inhibitors of epidermal growth factor receptor-tyrosine kinase (EGFR-TK) which blocks ATP-induced EGFR phosphorylation and subsequent signal transduction pathways involved in proliferation, metastasis, angiogenesis and apoptosis inhibition. High response rate with gefitinib in patients with activating mutations of EGFR.
-Resistance due to Kras mutations and cellular tyrosine kinase mutations.
-Tox: interstitial lung disease (
-MOA-A humanized mAb against VEGF (dimeric glycoprotein) that inhibits its interaction with VEGF receptors. VEGF is angiogenic, so Bevacizumab inhibits angiogenesis in tumors.
-Used to treat NSCLC, colon, and renal cancer.
-Toxicities include severe hypertension, proteinurea, congestive HF, pulmonary hemorrhage, thromboembolic events (stroke, MI) and gastric perforation.
-MOA-An important new folate analog, pemetrexed, is avidly transported into cells via the reduced folate carrier. It readily is converted to polyglutamates that inhibit thymidylate synthase (pyrimidine synthesis) and glycine amide ribonucleotide transformylase (GART in purine synthesis), as well as dihydrofolate reductase (DHFR). Unlike methotrexate, it produces little change in the pool of reduced folates, indicating that the distal sites of inhibition (TS and GART) predominate.
-Resistance: loss of influx transport, TS amplification, changes in purine biosynthetic pathways, or loss of polyglutamation.
-Tox: Pemetrexed toxicity mirrors that of methotrexate (myelosuppression, stomatitis, nephrotoxity), with the additional feature of a prominent rash in 40% of patients. Used against ovarian cancer and non–small cell adenocarcinomas of the lung.
Vincristine & Vinorelbine
-MOA-Interferes with microtubule function, resulting in impaired mitosis.
-Uses: Acute lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, Wilms’ tumor, neuroblastoma. Vinorelbine is used in non-small cell lung cancer and breast cancer.
-Tox: Neurotoxicity with peripheral neuropathy, paralytic ileus, myelosuppression, alopecia, inappropriate ADH secretion