cancer drugs

Question 1

draw the cancer drugs as they relate to the cell cycle (pg 401)

Answer 1

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.

Question 2

antineoplastics: draw the schematic and relevant drucs. basically starts with nucleotide synthesis

Answer 2

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.

Question 3

how are methotrexate and 5-FU related, mechastically?

Answer 3

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

Question 4

methotrexate: mechanism, toxicity

Answer 4

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

Question 5

5-fluoruracil: mechanism and toxicity

Answer 5

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

Question 6

cytarabine: mechanism and toxicity

Answer 6

pyrimidine analog that inhibits DNA pol. causes pancytopenia
S phase specific

Question 7

azathioprine and similar drugs: mechanism and toxicity, special uses

Answer 7

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

Question 8

dactinomycin: mechanism, toxicity

Answer 8

intercalates DNA.

myelosuppression

Question 9

bleomycin: mechanism, toxicity

Answer 9

induces free radical formation, which causes breaks in DNA strands.
pulmonary fibrosis, mucositis (skin changes). minimal myelosuppression
Gs phase.

Question 10

busulfan: mechanism, toxicity

Answer 10

cross-links DNA. may cause severe myelosuppression, pulmonary fibrosis, hyperpigmentation.

Question 11

vincristine, vinblastine: mechanism, toxicity

Answer 11

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.

Question 12

paclitaxol: mechanism, toxicity

Answer 12

hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down. (anaphase cannot occur).
causes myelosuppression, alopecia, hypersensitivity

Question 13

cisplatin, carboplatin: mechanism, toxicity

Answer 13

cross-link DNA. cause nephrotoxicity and acoustic nerve damage. prevent nephrotoxicity with amifostine (free radical scavanger) and chloride diuresis

Question 14

etoposide: mechanism, toxicity, similar drug

Answer 14

inhibits topoisomerase II- increases DNA degradation.
S and G2. causes myelosuppression, GI irritation, alopecia
also teniposide

Question 15

irinotecan: mechanism, toxicity

Answer 15

inhibit topoisomerase I and prevent DNA unwinding and replication. severe myelosuppression and severe diarrhea.
also topotecan

Question 16

nitrosoureas mechanism, toxicity

Answer 16

require bioactivation. cross BBB. cross-link DNA. cause CNS toxicity (convulsions, dizziness, ataxia).
examples: carmustine, lomustine, semustine, streptozocin)

Question 17

doxorubicin

Answer 17

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.

Question 18

cyclophosphamide, ifosfamide

Answer 18

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.

Question 19

alkylating agents

Answer 19

cyclophsophamide, ifosfamide, nitrosoureas (carmustine, lomustine, semustine, streptozocin), busulfan