06 Anticancer drugs Flashcards
Therapeutic modalities
Surgery and radiation therapy: localized, solid tumor
Drug therapy: systemic
Cell cycle drugs
CELL CYCLE-SPECIFIC DRUGS
kills cells within cell cycle
toxicity is proportional to the length of exposure, schedule specific
Methotrexate (s phase specific)
High growth fraction (ex. leukemia and lymphoma)
CELL CYCLE NON-SPECIFIC kills cells in and out of cell cycle toxicity is dose-dependent high and low growth fraction tumors alkylating agents and antitumor antibiotics except bleomycin
Gompertzian growth
Growth is fast but it slows down as time passes
cells compete for common/limited blood supply
advanced cancers are less responsive to chemo
Debulking procedure: surgery lessens tumor, remaining cells are stimulated to proliferate again = more sensitive to drugs
Gompertzian growth graph: diagnosis at 10^9-10^10 (too late), early diagnosis,
Cardinal rule of chemo: curability is inversely proportional to cell number
Cell kill
Log-kill or log cell-kill: A constant fraction of cells is given drug dose, not by a constant number
drugs used in chemo cannot be given continuously
Log cell-kill graph: surgery + adjuvant chemotherapy vs chemo vs late diagnosis with chemo
Factors affecting cell kill
Dose intensity and schedule: cannot tolerate -> reduce/delay dose
Drug resistance
Tumor site
Performance status
Drug selection
Single drug: choriocarcinoma, burkitt’s lymphoma
Combination: circumvents drug resistance, maximizes tumor cell kill
Guidelines: each drug should have some effectivity, different MOAs to prevent resistance, minimal overlapping toxicities
Lung = ECV
Breast = CMF
Acute lymphoblastic leukemia = COAP
General toxicity
Myelosuppression
dose-limiting toxicity
leukopenia > thrombo > anemia
exception: vincristine, bleomycin, streptozocin, hormones, asparaginase, cisplatin
Nausea and vomiting: CNS in origin, serotonin antagonists
Cytotoxicity to other cells: stomatitis, diarrhea, alopecia, infertility
Mechanism of acquired resistance
Improved DNA repair Dec in drug activation inc in drug inactivation dec in cellular uptake inc in p-glycoprotein -> inc in efflux
Antimetabolites: folic acid analogs
MOA: Activated intracellularly by FPGS -> polyglutamate metabolites
inhibit thymidylate synthesis
inhibit de novo purine synthesis
inhibit AA synthesis (serine and methionine)
PemeTREXed, pralaTREXate
MethoTREXate:
MOA: competes for folic acid in DHFR -> inhibit thymidylate and purine synthesis -> inhibition of DNA, RNA, protein synthesis
parenteral form, but not cross BBB (administer in subarachnoid space)
Toxicity: leucovorin
Antimetabolites: purine and pyrimidine analogs
1 Mercaptopurine (purine):
MOA: needs HGPRT -> monophosphate (inhibits de novo synthesis) + triphosphate (replaces guanine)
oxidized in liver by xanthine oxidase
allopurinol: xanthine oxidase inhibitor (= lessen dose of 6MP)
2 Thioguanine (purine)
3 Fluorouracil (pyrimidine): MOA: FdUMP = binds to an inhibits thymidylate synthase -> death FUTP = in RNA FdUTP = in DNA
4 Cytarabine (pyrimidine): MOA: block DNA synthesis and incorporate into DNA and RNA for hematologic malignancies
5 Gemcitabine:
MOA: block DNA synthesis, for solid and hematologic malignancies
Alkylating agents
MOA: form covalent bond with electron rich site -> DNA fragmentation (N7 site of guanine -> depurination and excision of guanine residues), cross-linking (no uncoiling prevents replication), mispairing
ANTman N Phoebe
Alkyl sulfonate, Nitrosoureas Triazine, Nitrogen mustards, Platinum coordination complexes
Nitrogen mustards
Cyclophosphamide
broadest spectrum
inactive -> liver -> cells -> cytotoxic phosphoramide and acrolein
oral, IV, IM
adverse: alopecia, sterile hematuria (accumulation of acrolein)
antidote: MSNa
Melphalan
Chlorambucil
Ifosphamide
Mechlorethamine
Adverse effects of alkylating agents
Bone marrow suppressio Vesicant effects (blistering) gonadal damage, azoospermia hemorrhagic cystitis nuerotoxicity pulmonary toxicity (fibrosis and death) nephrotoxicity mutagenic, carcinogenic, teratogenic
Cytotoxic antibiotics
MOA:
1 bind to DNA via intercalation 2 blocking DNA/RNA synthesis
3 DNA strand scission (generate free radicals and complex with topoisomerase II)
Adverse effects: tissue irritation, local tissue necrosis, cardiotoxicity (superoxide dismutase for free radicals), blisters, erythema, pulmo toxicity, mucocutaneous reactions, radiation recall reaction
Anthracycline, bleomycin
Adriamycin flare (-rubicin drugs): erythematous leak oven skin
rubicin: red urine and sclera
mitoxantrone: blue urine and sclera
Natural products
Mitotic inhibitors: act on M-phase
vinca alkaloids: VINcristine, VINblastine
taxanes: pacliTAXel, doceTAXel
Topoisomerase inhibitor:
camptothecins: irinotecan, topotecan
podophyllotoxins: etoposide, teniposide
