COMBINING POLYAMINE DEPLETION WITH RADIATION-THERAPY FOR RAPIDLY DIVIDING HEAD AND NECK TUMORS - STRATEGIES FOR IMPROVED LOCOREGIONAL CONTROL

Purpose: Locoregional control is adversely affected as clonogens from rapidly proliferating tumors repopulate during a course of radiation therapy. The cytostatic agent alpha-difluoromethylornithine (DFMO) was investigated for its capacity to slow proliferation kinetics in human squamous cell carcinomas (SCC) of the head and neck (H&N), with the ultimate objective of improving locoregional control in rapidly dividing tumors treated with radiation therapy. Methods and Materials: Three human SCC cell lines established from primary H&N tumors were evaluated in vitro (cell culture) and in vivo (SCC tumor xenografts in athymic mice) for the capacity of DFMO to induce growth inhibition. Flow cytometry analysis of SCC tumor growth kinetics and quantitative assessment of polyamine biosynthesis inhibition was performed to verify DFMO activity. DFMO effects on in vitro SCC radiosensitivity using clonogenic survival were also studied. Results: A noncytotoxic exposure to DFMO (5mM X 72 hours) induced pronounced growth inhibition in all three SCC cell lines (70-90% at 7 days), and induced a 2-3 fold delay in volume doubling time for SCC tumor xenografts when administered orally in the drinking water (1.5%) to athymic mice. Kinetic analysis via flow cytometry confirmed that DFMO produced a lengthening of SCC cell cycle times, but did not alter in vitro radiosensitivity. Inhibition of ornithine decarboxylase (ODC) activity and depletion of endogenous polyamines (putrescine and spermidine), were confirmed in normal tissue (mouse skin) and in human SCC tumor xenografts of athymic mice receiving continuous oral DFMO. Conclusion: These data indicate that antiproliferative agents, such ag DFMO, are capable of altering human SCC growth kinetics without altering intrinsic radiosensitivity. Such kinetic modulation may therefore provide a strategy to reduce the adverse impact of tumor cell proliferation during a radiotherapy treatment course for rapidly dividing tumors such as those in the H&N.