INHIBITION OF THE GROWTH OF HUMAN-COLON CANCER XENOGRAFTS BY POLAR-SOLVENTS

Abstract

The effects of N,N-dimethylformamide (DMF) and N-methylformamide (NMF) on the growth of 2 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% LD [LD10] 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 LD10 of DMF (daily for 21 days) or NMR (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 2-14%, within the acceptable range for LD10 doses. Some human cancer xenografts apparently respond to the polar solvent DMF and to its metabolite NMF; DMF may be acting at least in part by its metabolism to NMF. The data should alert clinical investigators to the possibility of hepatotoxicity when polar solvents are tested in Phase I [human] clinical trials.