Chemotherapy Flashcards
Cyclophosphamide
Class: chemical derivative of mechlorethamine (alkylating agent), cell cycle nonspecific.
Indication: most widely used of the alkylating agents, a variety of hematologic and solid tumors.
PK: given either iv (higher dose) or po, must be activated by hepatic p450 system. Eliminated by hepatic metabolism (3/4) and kidney (1/4)
Side effect: hemorrhagic cystitis, caused by the metabolite acrolein that is secreted in urine. Prevented by aggressive hydration or MESNA (2-mercaptoethanesulphonate) that binds and inactivates acrolein in the urine.
Mechlorethamine (Nitrogen Mustard)
Class: a “bi-functional” alkylating agent
PK: rapid IV infusion, topical application, rapidly degraded by non-enzymatic hydrolysis and therefore does not require dose adjustment in renal or hepatic failure.
Indication: cutaneous T-cell neoplasm
Side effects: severe nausea, vomiting and alopecia. Myelosuppression is dose-limiting.
Special: first chemotherapeutic agent, alkylating agents assoc with high incidence of 2’ cancer (esp. Leukemia, lymphoma, MDS)
Cisplatin
Class: bifunctional alkylating agent
PK/MOA: enters cells by passive diffusion then becomes ionized, binds to DNA to form interstrand and intrastrand cross links, cell-cycle specific
Indication: widely used in lung, breast, ovarian, head, neck cancers
Side effects: renal insufficiency (renal tubular cell damage), neuropathy (schwann cell killing and subsequent demyelination). Both reversible.
Ondansetron (Zofran)
Class: selective serotonin receptor (5HT3) blocking agent
MOA: blocks 5HT stimulation of vagal nerve, also by blocking CNS serotonin receptors
PK: iv, po approx 1/2hr before chemo
Indication: emetogenic side effects of chemotherapy
Special: can be combined with steroids for maximal benefit, aprepitant, an nerokinin 1 agonist that blocks substance P binding is a new antiemetic that can be combined with 5-HT inhibitors.
Methotrexate
Class: anti-metabolite, direct descendant of aminopterin
MOA: analogue of folic acid (i.e. Folate, dihydrofolate) and inhibits DHFR by competitive inhibition
Indication: lymphoma, breast cancer, head, neck, lung cancer, often intrathecally to treat CNS cancer, rheumatoid arthritis and lupus, prevention of GVHD at low dose/immunosuppression
PK: wide range of uses–from low dose, oral immunosuppression, to very high, iv dosing
Side effects: marrow suppression, GI toxicity (mucositis, diarrhea), and renal failure, caused by precipitation of the drug in renal tubules
Special: MTX can be given at very high dose to achieve greater tumor cell kill, must be followed by leucovorin rescue to prevent lethal side effects (renal failure, marrow failure, gut sloughing, the above, but much worse), tumor cell become resistant to MTX by decreased transport, gene amplification, and mutation of DHFR
5 Fluouracil (5FU)
Class: anti-metabolite
MOA: inhibits enzyme thymidylate synthase by a suicide mechanism
Indication: breast and GI malignancies
Side effects: bone marrow, GI toxicity
Special: leucovorin is used to potentiate the action of 5FU by providing more substrates (i.e. N5N10 methylene-THF) to thymidylate synthase.
Cytarbine (ara-C)
Class: nucleoside analogue of cytidine.
MOA: sugar moeity changed from ribose to arabinose, taken into cell and metabolized just as the normal compound. Once converted to ara-CTP it binds and competitively inhibits DNA pol a, interfering with DNA replication, can act to slow chain elongation and inhibits DNA ligation. S-phase specific
Indication: AML, lymphoma
PK: continuous iv infusion for seven days as part of AML induction chemotherapy along with Daunarubicin, and at much higher doses bid for three days (7 + 3 regimen)
Side effects: marrow aplasia, GI toxicity, alopecia, high dose daunarubicin also causes acute severe cerebellar toxicity
Daunarubicin, Doxorubicin, Idrarubicin
Class: Anthracycline Antibiotics
MOA: inhibition of topoisomerase II, anthracyclines stabilize a DNA-TopoII intermediate and inhibit religation of DNA ends, resulting in DNA fragmentation and cell death, drugs consist of sugar molecule attached to a tetracycline backbone, able to intercalate into DNA, inhibiting DNA replication and mRNA synthesis.
Indication: hematologic neoplasm, breast, lung, GI, GU cancer
PK: hepatic metabolism, decrease dose in liver failure
Side effects: GI, marrow, cardiomyopathy (reversible, subjective to CHF and arrythmia, no specific treatment), the anthracyclines are vesicants
Topotecan, Irinotecan
Class: topoisomerase I inhibitor
MOA: prevent religation of DNA fragments, activating DNA damage-dependent apoptosis pathways.
Indication: lung, ovarian, colorectal cancer
Side effects: diarrhea could be life-threatening
Vincristine, Vinblastine
Class: anti-cancer
MOA: bind specifically to tubulin preventing microtubule assembly, block M-phase specific cell division and induce apoptosis.
Indications: lymphoma, sarcoma, breast, lung, cervix (Vincristine), lymphoma, testicle (vinblastine)
Toxicity: neuropathy (Vincristine), bone marrow (Vinblastine)
PK: hepatic metabolism
Special: vincristine is particularly useful when combined with other drugs whose primary toxicity is in bone marrow.
Taxol
Class: anti-cancer
MOA: like chemically similar vinca alkaloids, taxol binds also to microtubules. Unlike vincas, it acts to stabilize microtubule structure preventing depolymerization and inducing apoptosis.
Indication: taxol has been found to have high degree of activity in breast, lung, ovarian cancers.
Velcade, Carfilzomib
Class: proteosomal inhibitor, anti-cancer
MOA: inhibit degradation of proteins leading to activation of unfolded protein stress pathway and hopefully apoptosis
Indication: multiple myeloma, mantle cell lymphoma
Thalidomide, Lenalidomide, Pomalidomide
Class: immunomodulatory drugs, anti-cancer
MOA: unclear
Thalidomide-teratogenic, used to treat leprosy, GVHD, multiple myeloma
Lenalidomide-more effective in myeloma, current standard of care in multiple myeloma, also used for mantle cell NHL and myelodysplastic syndrome, causes peripheral neuropathy
Pomalidomide-approved for use in multiple myeloma
Special: due to risk of birth defects, pt must enroll in program that closely follows them while on therapy
Rituxin (Rituximab)
Class: anti-cancer
MOA: targets CD20 present on pre-B and B lymphocytes and mostly B cell NHL (Non-hodgkins lymphoma), Fc-mediated phagocytosis, complement-mediated cytotoxicity, apoptosis induction
PK: administered iv on a weekly schedule
Indication: response rates of approx 50% in pts who had failed standard chemotherapy, when given with CHOP to pts with NHL improved CR rates
Special: the first humanized monoclonal ab approved for human use
C.f. Gemtuzumab (Ozogamicin)-targets CD33, immature myeloid cells, indicated for AML, Tiuxetan (Zevalin)–used to treat NHL, Cetuximab (Erbitux)-targets EGFR, treats Colorectal, Head/Neck, Bevacizumab (Avastin)-targets VEGF, treats colorectal, lung, breast, kidney, glioblastoma
5-Azacytidine
Class: anti-cancer, hypomethylating agent
MOA: targets DNA methylation moiety, induces cellular differentiation, modulates genomic DNA methylation
Indication: AML, MDS
