Antineoplastic agents Flashcards
Alkylating Agents
Nitrogen mustards
Cyclophosphamide
Ifosfamide
Alkylating Agents
Alkyl sulfonate
Busulfan
Alkylating Agents
Platinum coordination complexes
Cisplatin
Natural Products
Vinca alkaloids
Vinblastine
Vinorelbine
Vincristine
Natural Products
Taxanes
Paclitaxel
Natural Products
Epipodophyllotoxins
Etoposide
Natural Products
Antibiotics
Doxorubicin
Natural Products
Anthracenedione
Bleomycin
Natural Products
Enzymes
L-Asparaginase
Antimetabolites
Folic acid analogs Methotrexate Pyrimidine analogs Fluorouracil (5-fluorouracil; 5-FU) Purine analogs Mercaptopurine (6-MP)
Rescue agents
Leucovorin
Mesna
Protein tyrosine kinase inhibitors
Imatinib
Monoclonal Antibodies
Trastusumab
Agents used to minimize adverse effects
Filgrastim
Erythropoietin or darbepoetin alfa
Serotonin antagonists
Ondansetron
Alkylating Agents MOA
Form covalent linkages with DNA
Specific alkylating agent toxicities
Cyclophosphamide – hemorrhagic cystitis
Cisplatin – renal tubular damage, ototoxicity
Busulfan – pulmonary fibrosis
Antimetabolites: 3 major classes
Folic acid analogs (methotrexate) Pyrimidine analogs (5-Fluorouracil) Purine analogs (6-mercaptopurine)
Antimetabolites MOA
Structural analogs to compounds necessary for cell proliferation
Block or subvert pathways that are involved in, or lead to, cell replication (nucleotide and nucleic acid synthesis)
Cell cycle specific (S phase)
Methotrexate
Inhibits dihydrofolate reductase (DHFR) Indications: Cancer Rheumatoid arthritis Psoriasis
Methotrexate & Leucovorin Rescue
Leucovorin: reduced folate can bypass DHFR
Used to rescue normal cells from high-dose MTX
Antidote for accidental MTX overdose
Pyrimidine Structural Analogs
Prototype: 5-Fluorouracil (5-FU)
Prodrug
Fluorouracil: Mechanisms of Action
Active compound (FdUMP) covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate
Active compounds (FdUTP and FUTP) are incorporated into both DNA and RNA, respectively
Leucovorin can’t rescue
Drug Interaction: 6-MP & Allopurinol
Biotransformation of 6-MP includes metabolism to the inactive metabolite 6-thiouric acid by xanthine oxidase (first pass effect)
Allopurinol, a xanthine oxidase inhibitor, is often used as supportive care in the treatment of acute leukemias to prevent hyperuricemia due to tumor cell lysis
Simultaneous administration of allopurinol and oral 6-MP results in increased levels of 6-MP and increased toxicity
Reduce oral 6-MP dose by 50-75%; IV dose unaffected
Antimetabolites: Pharmacodynamics
Cell cycle specific (S-phase)
Relatively little acute toxicity after an initial dose
Oral, intravenous, intrathecal (methotrexate) are common routes of administration
Common toxicities include diarrhea, myelosuppression, nausea, vomiting, immunosuppression, thrombocytopenia, leukopenia, hepatotoxicity
Vinca Alkaloids: Adverse Effects
Alopecia
Myelosuppression (vinblastine > vincristine)
Vincristine exhibits neurotoxicity (numbness and tingling of the extremities, loss of deep tendon reflexes, motor weakness, autonomic dysfunction has also been observed)
Vinca Alkaloids: Mechanism of Action
Bind to β-tubulin and inhibit microtubule assembly
Cell cycle specific mitosis inhibition (M-phase)
Taxanes: Mechanism of Action
Bind to β-tubulin and stabilize microtubule assembly
Cell cycle specific mitosis inhibition (M-phase)
Taxanes: adverse effects
Paclitaxel
Hypersensitivity reactions in hands and toes, change in taste
Docetaxel
Greater cellular uptake; retained intracellularly longer than paclitaxel permitting smaller dose, which reduces AEs
Hypersensitivity, neutropenia, alopecia
Topoisomerase Inhibitors
Type I
Type II - Inhibitors:
Epipodophyllotoxins (etoposide, teniposide)
Anthracycline antibiotics (doxorubicin, daunorubicin)
Cell cycle specific (primarily S phase, also G1 and G2)
Anthracyclines: MOA
Inhibit topoisomerase II
Intercalate DNA
Oxygen free radicals bind to DNA causing single- and double-strand DNA breaks
Cell cycle nonspecific (but cycling cells are more susceptible)
Free radicals are linked to significant cardiotoxicity
Cumulative cardiac damage can lead to dysrhythmias and heart failure
Antitumor Antibiotics: Bleomycin
MOA: Free radicals cause single- and double-strand DNA breaks
Cell cycle specific (G2 arrest)
Causes minimal myelosuppression – useful in combination
Can cause significant pulmonary toxicity (5-10%, usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles)
Antineoplastic Enzymes
L-aspariginase
MOA: hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
Cell cycle specific (G1)
Antineoplastic Enzymes: Adverse effects
Acute hypersensitivity reaction
Delayed toxicities include an increased risk of clotting and bleeding, pancreatitis, and CNS toxicity including lethargy, confusion, hallucinations, and coma
Antineoplastic Enzymes: Indication
Targeted therapy for acute lymphoblastic leukemia (ALL)
ALL tumor cells lack the enzyme asparagine synthetase and thus require an exogenous source of L-asparagine
Erlotinib and Gefitinib
MOA: Inhibit Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase
Preferred single-agent first-line therapy for NSCLC patients with somatic activating EGFR mutations
Produce dermatologic toxicities
Bcr-Abl, CML, and Imatinib (Gleevec)
The BCR-ABL fusion protein results from the t(9:22) translocation and is found in 95% of patients with CML
Imatinib is a small molecule inhibitor of the ABL tyrosine kinase and has been hailed as a conceptual breakthrough in targeted chemotherapy
Imatinib can also inhibit the RTKs PDGFR and c-KIT
