Effects of alpha-difluoromethylornithine and recombinant interferon-alpha 2 on the growth of a human renal cell adenocarcinoma xenograft in nude mice.
The effects of human recombinant interferon-alpha 2 (IFN-alpha 2) and alpha-difluoromethylornithine (DFMO) as single agents and in combination were studied for efficacy against the renal cell adenocarcinoma (JDF-1) in an in vitro clonogenic assay and in vivo as xenografts in nude mice. In vitro studies showed dose-dependent inhibition of JDF-1 colony formation by IFN-alpha 2. DFMO alone did not significantly inhibit colony formation even though ornithine decarboxylase activity was significantly inhibited. The combination of IFN-alpha 2 and DFMO synergistically inhibited JDF-1 colony formation. The synergism was more readily observed at low IFN-alpha 2 concentrations. In vivo studies showed a similar tumor growth inhibition pattern. JDF-1 tumors were implanted s.c. in nude mice, and drugs were administered continuously by Alza minipumps (IFN-alpha 2) and in drinking water (DFMO) for 28 days. IFN-alpha 2 alone significantly inhibited JDF-1 growth, while DFMO alone had no significant inhibitory effect. The combination of IFN-alpha 2 and DFMO inhibited tumor growth in an apparent additive manner at the doses used. This was reflected in the mean tumor weights obtained at the termination of the experiment: control, 1484 +/- 187 (S.E.) mg; DFMO only, 1106 +/- 129 mg; IFN-alpha 2 only, 941 +/- 186 mg; and DFMO plus IFN-alpha 2, 620 +/- 109 mg. Assessment of mouse natural killer cell activity at the time of sacrifice showed that DFMO inhibited natural killer cell activity, while IFN-alpha 2 had no effect. DFMO was observed to inhibit ornithine decarboxylase activity in JDF-1 tumors by 78%, IFN-alpha 2 by 18%, and the combination by 78%. In addition, the drugs individually and in combination had similar inhibitory effects on JDF-1 spermidine content. One of the unexpected findings was the alteration in the spermine:spermidine ratio in the tumors treated with the combination of DFMO and IFN-alpha 2. The ratio in this group decreased to 0.44, while ratios for control, IFN-alpha 2 only, and DFMO only were 0.99, 0.66, and 0.88, respectively. These results clearly show that combined therapy with DFMO and IFN-alpha 2 is more effective than is single-drug therapy. The mechanism by which these drugs coordinately inhibit tumor growth is unclear but appears to be associated with direct inhibition of tumor cell proliferation, possibly by modulation of polyamine metabolism.
D000230:Adenocarcinoma / Q000503:physiopathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D004357:Drug Synergism; D000518:Eflornithine; D006801:Humans; D007370:Interferon Type I / Q000633:toxicity*; D007680:Kidney Neoplasms / Q000503:physiopathology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009952:Ornithine / Q000031:analogs & derivatives* / Q000633:toxicity; D011073:Polyamines / Q000032:analysis; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D007370:Interferon Type I; D011073:Polyamines; D009952:Ornithine; D000518:Eflornithine