Inhibition of the growth of human colon cancer xenografts by polar solvents.
The effects of N,N-dimethylformamide (DMF) and N-methyl-formamide (NMF) on the growth of two human colon cancer cell lines xenografted in nude mice were assessed. Toxicological studies with mice heterozygous for the nu/nu gene showed that with both compounds the limiting organ toxicity was hepatic. The 10% lethal doses for DMF and NMF given i.p. daily for 21 days were 2219 and 374 mg/kg, respectively. Nude mice (10/group) received s.c. transplants of HCT-15 or DLD- 2 human colon cancer cells. Mice were treated i.p. with the approximate 10% lethal doses of either DMF (daily for 21 days) or NMF (daily for 19 days) or with 0.9% NaCl solution when tumors became palpable. With the HCT-15 tumor, a growth inhibition of 65% was obtained using DMF compared to 0.9% NaCl solution-treated controls. Two independent experiments with DLD-2 demonstrated that DMF effected growth inhibitions of 45 and 67%. NMF treatment produced 48 and 75% growth inhibitions of HCT-15 and DLD-2 tumors, respectively. Weight loss of groups of treated mice in all experiments was between 2 and 14%, within the acceptable range for 10% lethal drug doses. Results indicate that some human cancer xenografts respond to the polar solvent DMF and to its metabolite NMF and that DMF may be acting at least in part by its metabolism to NMF. Furthermore, the data should alert clinical investigators to the possibility of hepatotoxicity when polar solvents are tested in Phase I clinical trials.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003110:Colonic Neoplasms / Q000503:physiopathology*; D004126:Dimethylformamide / Q000494:pharmacology*; D005260:Female; D005559:Formamides / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012997:Solvents / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D005559:Formamides; D012997:Solvents; D004126:Dimethylformamide; C002950:methylformamide