1. for chlorethylamine drugs, active immonium intermediate produced from drug which interacts primarily with DNA guanine at N7 poistion
2. second chloroethylamine group crosslink two DNA chains
   1. prevents DNA chain separation and cell replication
   2. produce base mispairing, deuprination, strand scission, decreased DNA synthesis and function

• mechlorethamine
• cyclophosphamide
• carmustine
• Cis-Platin

1. activated by liver P450 enzymes to form intermediate 4-hydroxycyclophosphamide
   • in normal tissue, deactivated via aldehyde dehydrogenase
   • no aldehyde DH in drug sensitive tumors (in resistant tumors, they may be high)
2. tumor tissue activates drug to phosphoramide mustard, which is the cytotoxic antitumor metabolite

• bladder toxicity, causing hemorrhagic cystitis (sometimes even tumors) due to its metabolite acrolein (found in urine)
  • prevent mensa (SH compounds)

• tumor growth suppression
• immunosuppression, so RA

• chemistry- nitrosurea
  • mech. ver similar to nitrogen mustard
• indication- brain tumor (very lipid soluble)

• indications- testicular and ovarian cancer (although extensively used, occasionally produce cure)
• mechanism similar to other alkylating agents
  1. produce platinum-DNA cross links
  2. interfere with DNA function
  3. also form Pt-DNA-protein crosslinks
• adverse effects
  • renaltoxicity
  • ototoxicity
  • neurotoxicity
  • much less myelosuppression than many other antitumor drugs
  • solution- hydration with saline and diuretic therapy

• decrease transport in tumor cells
• repair via reversal (excision) of drug-DNA alkylation
  • cross R btw subclasses of alkylating agents possible (but not nitrosoureas and chlorethamine)
  • via increase in GOAT enzyme, we dealkylate guanine
• increase levels of detoxifying SH compounds which will interact with alkyl drugs and inactivate them

1. inhibits DHFR
2. leads to decrease in tetrahydrofolates
   • decrease de novo formation of purines for DNA and RNA synthesis
   • inhibit thymidylate synthase, leading to decrease dTMP and decrease DNA synthesis

• it is a form of tetrahydrofolate that allows us to bypass the inhibited DHFR caused by MTX
• this will allow for an increase in MTX dosage which will increase tumor kill by allowing for:
  • enhanced formation of intratumoral MTX-polyglutamate (its active anti-tumor metabolite)

• at normal doses, via active transport into tumor
• at high doses, via simple diffusion (we have overwhelmed the active transport mechanism)

• via gene amplification, we can increase levels of DHFR (major)
• decrease active transport of MXT into tumor cells
• mutation of DHFR
• decrease ability to form MTX-polyglutamate in tumor

• anticancer
• immunosupprssive
  • RA
  • psoriasis

• 5-fluorouracil
• cytarabine (ara-C)

1. tumor cells will preferrentially incorperate uracil
2. uracil anabolized to FdUMP or FUMP
   • FdUMP inhibits thymidiylate synthase, preventing formation of TMP and inhibiting DNA synthesis, allowing for major tumor inhibition by FU by forming FdUMP-TS-methylene FH₄
3. leads to incorperation into RNA and DNA
4. interfers with nucleic acid function

• mechanism of toxicity: low levels of DHPD (inherited deficiency)
  • serious hematopoietic, GI, CNS toxicity from standard dosing
• solution- genetic testing, then dosage adjust

• failure to anabolize FU to active intermediate
• increase TS
• repair FU containing nucleic acids

1. metabolically activated to mono/di/tri phosphate (mainly ara-CTP)
   • incorperate into DNA of susceptible tumors (those high in ara-CTP) and DNA is now defective, nonfunctional, and cytotoxic
   • inhibit DNA polymerase by competing with dCTP (no DNA polymerization)
   • inhibit S phase (inhibits DNA synthesis)
2. rapidly catabolized to corresponding uracil compounds (ara-U and ara-UMP) that are inactive metabolites

Antitumor activity directly related to levles of triphosphate: ara-CTP.

• diminished drug phosphorylation (aka anabolism)
• increase deactivation to ara-U
• mutated DNA polymerase not inhibited by ara-CTP

• short half life
  • requires that we readminister dosing frequently
  • we need high ara-CTP concentration during several S phases

• 6-mercaptopurine
• 6-thioguanine

1. activated to TIMP
2. further conveted to thio-GMP
3. converted to thio-containing RNA/DNA
4. block tumor growth (also cause toxicity)

1. TIMP via TPMT will inhibit de novo purine synthesis, but will lead to its inactivation

• if you have low levels of TPMT, it will lead to extensive myelosuppresion and hepatotoxicity
  • solution- precautionary genetic testing and dosage adjustment

competition between activation and inactivation rxns

1. activated directly to T-GMP
2. then activating to thiocontaining RNA/DNA to produce anti-tumor activity

• reduced anabolism
• reduce cell penetration
• more rapid degradation of 6MP and 6TG and their phosphorylated metabolites

• mechanism
  1. inhibits xanthine oxidase
  2. leads to decrease uric acid formation, protecting cancer pts from hyperuricemia
• if pt receiving allopurinol, must greatly reduce dose of 6-MP to avoid serious toxicity from raised concentrations of toxic 6-MP metabolites