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Successful treatment with DL-alpha-difluoromethylornithine in established human small cell variant lung carcinoma
Abstract:
We report that p.o. administration of DL-alpha-difluoromethylornithine (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 less than 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 less than 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 less than 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.
Insights
DL-alpha-difluoromethylornithine (DFMO) significantly inhibits human small cell lung carcinoma (SCC) growth in mice. Early DFMO treatment showed a 99% tumor reduction, suggesting potential for low tumor burden SCC treatment.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Small cell lung carcinoma (SCC) is an aggressive cancer with limited treatment options.
- Polyamines are essential for cell growth and proliferation, making their biosynthesis a target for cancer therapy.
- DL-alpha-difluoromethylornithine (DFMO) is a specific inhibitor of ornithine decarboxylase, a key enzyme in polyamine biosynthesis.
Purpose of the Study:
- To evaluate the efficacy of DFMO in inhibiting the growth of human SCC xenografts in athymic nude mice.
- To determine the impact of DFMO treatment timing (early vs. late) on tumor growth inhibition and animal survival.
- To assess the potential clinical utility of DFMO as a therapeutic agent for SCC.
Main Methods:
- Human SCC cells were implanted subcutaneously into athymic nude mice.
- Tumor-bearing mice were randomized into control, early DFMO treatment, and late DFMO treatment groups.
- DFMO was administered orally via drinking water at a dose of 5.0 g/kg/day.
- Tumor volume and animal survival were monitored over a 9-10 week period.
Main Results:
- DFMO treatment significantly inhibited SCC tumor growth in a dose-dependent manner.
- Early DFMO treatment (low tumor burden) resulted in 99% tumor growth inhibition and prolonged median survival to 15 weeks.
- Late DFMO treatment (high tumor burden) resulted in 60% tumor growth inhibition and prolonged median survival to 14 weeks.
- No significant clinical toxicities were observed in DFMO-treated mice during the study period.
Conclusions:
- DFMO demonstrates significant antitumor activity against human SCC in a preclinical model.
- Early intervention with DFMO appears more effective, suggesting its potential utility in patients with low tumor burden.
- DFMO may serve as a valuable agent for maintaining remissions induced by combination chemotherapy in SCC patients.