cancer drugs Flashcards
draw the cancer drugs as they relate to the cell cycle (pg 401)
M phase (mitosis): vinca alkaloids (vincristine, vinblastine) and taxols (paclitaxel) G 1 phase (synthesis of components needed for DNA syntheisis)/Go (resting): no drugs S phase (DNA synthesis): antimetabolites (methotrexate, 5-FU, cytarabine, azathioprine, 6-mercaptopurine, 6-thioguanine), etoposide G2 phase (synthesis of components needed for mitosis): bleomycin, etoposide.
antineoplastics: draw the schematic and relevant drucs. basically starts with nucleotide synthesis
nucleotide synthesis –> DNA –> RNA –> protein –> cellular division
nucleotide synthesis: inhibited by methotrexate/5-FU (prevent thymidine synthesis). 6-mercaptopurine (probably azathioprine and 6-TG too) prevent purine sythesis. (probably cytarabine too)
DNA: alkylating agents (ifosfamide, cyclophosphamide, busulfan, nitrosoureas like carmustine, lomustine, semustine, streptozocin), cisplatin: cross link DNA
dactinomycin and doxorubicin: DNA intercalators
etoposide: inhibits topoisomerase II.
cellular division: vinca alkaloids inhibit microtubule formation; paclitaxel inhibits microtubule disassembly.
how are methotrexate and 5-FU related, mechastically?
dUMP must be converted to dTMP as part of DNA synthesis. this is done by thymidylate sythase enzyme. it requires the CH2-THF cofactor, which is converted to DHF.
thymidylate synthase is inhibited by 5-FU.
To restore CH2-THF, from DHF, DHF is converted to THF by dihydrofolate reductase. THF is converted to CH2-THF. methotrexate inhibits dihydrofolate reductase
see pic on pg 403
methotrexate: mechanism, toxicity
folic acid analog that inhibits dihydrofolate reductase: decr. dTMP, decr. DNA and protein sythesis.
toxicity: myelosuppression. reversible with leucovorin (folinic acid) rescue. also macrovesicular fatty change in liver and mucositis
S phase specific
5-fluoruracil: mechanism and toxicity
pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. this complex inhibits thymidylate synthase- decr. dTMP, decr. DNA and protein sythesis.
causes myelosuppression. not reversible with leucovorin. rescue from overdose with uridine
S phase specific
cytarabine: mechanism and toxicity
pyrimidine analog that inhibits DNA pol. causes pancytopenia
S phase specific
azathioprine and similar drugs: mechanism and toxicity, special uses
others: 6-mercaptopurine, 6-thioguanine.
purine analogs that decr. de novo purine synthesis. activated by HGPRT.
note that they are also used in RA; azathioprine used in SLE
toxic to bone marrow, GI, liver. azathiprine and 6-MP are metabolized by xanthine oxidase, so both have increased toxicity with allopurinol.
S phase specific
dactinomycin: mechanism, toxicity
intercalates DNA.
myelosuppression
bleomycin: mechanism, toxicity
induces free radical formation, which causes breaks in DNA strands.
pulmonary fibrosis, mucositis (skin changes). minimal myelosuppression
Gs phase.
busulfan: mechanism, toxicity
cross-links DNA. may cause severe myelosuppression, pulmonary fibrosis, hyperpigmentation.
vincristine, vinblastine: mechanism, toxicity
vinca alkaloids that bind beta-tubulin. that inhibits its polymerization into microtubules and prevents mitotic spindle formation (M-phase).
vincristine: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus.
vinblastine: bone marrow suppression.
paclitaxol: mechanism, toxicity
hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down. (anaphase cannot occur).
causes myelosuppression, alopecia, hypersensitivity
cisplatin, carboplatin: mechanism, toxicity
cross-link DNA. cause nephrotoxicity and acoustic nerve damage. prevent nephrotoxicity with amifostine (free radical scavanger) and chloride diuresis
etoposide: mechanism, toxicity, similar drug
inhibits topoisomerase II- increases DNA degradation.
S and G2. causes myelosuppression, GI irritation, alopecia
also teniposide
irinotecan: mechanism, toxicity
inhibit topoisomerase I and prevent DNA unwinding and replication. severe myelosuppression and severe diarrhea.
also topotecan
nitrosoureas mechanism, toxicity
require bioactivation. cross BBB. cross-link DNA. cause CNS toxicity (convulsions, dizziness, ataxia).
examples: carmustine, lomustine, semustine, streptozocin)
doxorubicin
generate free radicals. interalate in DNA causes breaks in DNA, decr. replication. cause cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. dexrazoxane used to limine cardiotoxicity. it is an iron chelating agent.
cyclophosphamide, ifosfamide
alkylating agent. covalently X-link DNA at guanine N7. require bioactivation by the liver. cause myelosuppression and hemorrhagic cystitis. prevent with Mesna or N-acetylcystein.
acrolein is the metabolite that is damaging to the bladder.
alkylating agents
cyclophsophamide, ifosfamide, nitrosoureas (carmustine, lomustine, semustine, streptozocin), busulfan
