Successful Treatment with DL-α-Difluoromethylornithine in Established Human Small Cell Variant Lung Carcinoma Implants in Athymic Mice

We report that p.o. administration of DL-α-dffluoromethylomithine (DFMO), a specific inhibitor of polyamine biosynthesis, markedly inhibits the growth of established implants of cultured human small cell lung carcinoma (SCC) in athymic (nude) mice. Human SCC tumor cells, from a cell line which exhibited cell death in culture in the presence of DFMO, were inoculated s.c. into athymic mice. The tumors were permitted to grow until they became palpable (0.05 cu cm, 3- to 5-mm-diameter nodules). The animals were then randomized into control, and early (low tumor burden) and late (high tumor burden) treatment groups which received 3% DFMO in the drinking water (5.0 g/kg/day). The tumors in the untreated control group grew to a size of 29 cu cm by 9 weeks, and these animals had a median survival of 9 weeks. The late treatment group began DFMO treatment 3 weeks after clinical tumor engraftment, when mean tumor size was 1.5 cu cm (1.2- to 1.5-cm-diameter nodules). Tumor growth was inhibited by 60% (11.4 cu cm) by Week 9 and survival was prolonged, with 83% survival at 10 weeks and a 56% increase in median survival to 14 weeks (p < 0.05). The early treatment group received the same dose of DFMO beginning 1 week after tumor engraftment, when their mean tumor size was 0.1 cu cm (4- to 6-mm-diameter nodules). The early DFMO group had a 99% inhibition in tumor growth (0.3 cu cm) (p < 0.05). Survival was also prolonged compared to the untreated controls, with 83% survival at 10 weeks and a median survival of 15 weeks (p < 0.05). In both the early- and late-DFMO-treatment groups, no significant clinical toxicities were observed in the first 10 weeks, during which antitumor therapeutic effects were seen. DFMO may have a potential role in the treatment of sensitive human tumors such as SCC. The data suggest that DFMO may be most useful clinically in patients with SCC who have a low tumor burden. Thus, DFMO might be an important tool to produce long-term maintenance of initial clinical remissions induced by combination chemotherapy.