Cancer drugs

Question 1

mechlorethamine

Answer 1

nitrogen mustard; spontaneously activated; nitrogen mustards intramolecularly form a carbonium ion intermediate to become activated. Then N7 of guanine nucleophilic attacks the unstable aziridine ring of the carbonium ion intermediate -> triggers apoptosis

Question 2

cyclophosphamide

Answer 2

nitrogen mustard; need hepatic CYPs for activation; then N7 of guanine nucleophilic attacks and form cross-links within and between DNA strands-> triggers apoptosis

Question 3

carmustine

Answer 3

Nitrosoureas; spontaneous degrades, then alkylates DNA and carbamoylates protein

Question 4

cisplatin

Answer 4

Platinum coordination complexes; Loses Cl- in a low chloride medium in exchange for OH. The platinum complex will then react with DNA causing intrastrand and interstrand crosslinks (i.e. guanine to guanine, guanine to adenine). This inhibits RNA synthesis.

Question 5

Methotrexate

Answer 5

anti-folate; mimics dihydrofolic acid, inhibits dihydrofolate reductase -> causes build up FH2 which feedback inhibits thymidylate synthase additionally; rescue host toxicity by reduced folate (leucovorin); retained in kidney for weeks and cause organ damage

Question 6

5-fluorouracil (5-FU)

Answer 6

pyrimidine analog; enters cells and must be converted to the corresponding nucleotide, either FUTP for RNA or FdUTP for DNA; An intermediate, FdUMP (fluorodeoxyuridine monophosphate), works as an inhibitor of thymidylate synthase; 5-FU incorporates into DNA and inhibits RNA processing

Question 7

cytarabine (cytosine arabinoside, Ara-C)

Answer 7

cytidine analog; Ara-C enters cells and must be converted to the corresponding nucleotide, Ara-CTP; has a C-2 OH group in the sugar in the trans position instead of cis. This interferes with base pairing.

Question 8

6-mercaptopurine (6-MP)

Answer 8

purine analog; 6-MP competes with hypoxanthine and guanine for HGPRT and becomes 6-thioinosinic acid (TIMP) -> Inhibits conversation of IMP to adenylsuccinic acid and xanthylic acid; additionally, the structure of TIMP is similar to AMP and GMP thus feedback inhibits the PRPP amidotransferase

Question 9

Taxol

Answer 9

antitubulin/antimitotic; binds and stabilizes microtubules

Question 10

Colchicine, colcemid, vinblastine, vincristine, nocodazole

Answer 10

antitubulin/antimitotic; binds subunits, sequesters free tubulin, prevents their polymerization

Question 11

Dactinomycin

Answer 11

antibiotic; cell cycle independent; binds to DNA helix to form a dactinomycin-DNA complex that blocks transcription of DNA by RNA polymerase; additionally causes single-strand breaks in DNA

Question 12

doxorubicin and daunorubicin

Answer 12

Anthracyclines and anthracenediones; binds to the persistent cleavage complex (topoisomerase II + DNA) to form a tripartite complex -> permanent double stranded break; additionally, quinione groups generate free radicals in solution (superoxide), which attack DNA and oxidize DNA bases -> high cardiac toxicity

Question 13

Etoposide, Teniposide (podophyllotoxin)

Answer 13

Epipodophyllotoxins; cell cycle dependent; form a ternary complex with topoisomerase II and DNA and prevent resealing of the break that normally follows topoisomerase binding to DNA -> accumulation of DNA breaks and cell death

Question 14

Bleomycin A2, Belomycin B2

Answer 14

Bleomycins; chelates copper and iron then acts through binding to DNA induces single and double stand breaks following free radical formation and inhibition of DNA synthesis; DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal abberations

Question 15

Imatinib

Answer 15

receptor tyrosine kinase inhibitor, in CML (t9;22), Abelsome kinase (9)-break point cluster (ABL-BCR) region chimera such that the kinase is constitutively on

Question 16

rapamycin

Answer 16

rapalog; mTOR inhibitor; shows patient-to-patient variation, tumors contain numerous mutations -> genetic heterogeneity in tumors