Cyclins and cyclin-dependent kinases (cdks) are dysregulated in cancer cells, and as such are potential targets in cancer therapy. Flavopiridol is a novel inhibitor of cdks, exhibits antitumor activity, and augments antitumor actions of chemotherapeutic agents. Recently, we reported that flavopiridol is a strong enhancer of in vitro sensitivity of murine ovarian cancer cells to ionizing radiation (Raju et al. Cancer Res., 2003). The present study investigated whether radiosensitizing properties of flavopiridol are a more general phenomenon. The effects of flavopiridol in combination with ionizing radiation were assessed using HN5 human head and neck squamous cell carcinoma and SEG-1 esophageal adenocarcinoma cells. The cytotoxic effects of these agents when used alone or in combination was determined by the in vitro clonogenic cell survival assay. Treatment of cells with 300 nM of flavopiridol for 1 day before the exposure of cells to graded doses of 2-6 Gy radiation resulted in significant enhancement of tumor cell radiosensitivity. Enhancement factors (EFs) were calculated at the surviving fraction of 0.1 (10% cell survival) by dividing radiation dose of the radiation only curve with that of the corresponding flavopiridol plus radiation curve. EF value for HN5 cells was 1.47 and that for SEG-1 cells was 1.63. Flavopiridol modified the shape of the cell survival curves of both cell types by almost completely removing the “shoulder” region on the survival curve, suggesting that inhibition of DNA repair is likely one of the mechanisms of the flavopiridol-induced enhancement of cell radiosensitivity. In addition, the inhibition of cdks by flavopiridol resulted in cell cycle redistribution in both cell types. Flow cytometry analysis showed that flavopiridol depleted cells in the radioresistant S-phase and increased the number of cells in relatively radiosensitive G-1 phase. Thus, cell cycle redistribution is likely another mechanism of flavopiridol-induced cell radiosensitivity. In conclusion, our results published previously and our findings presented here imply that flavopiridol has broad-range activity in enhancing radiosensitivity of cancer cells of both rodent and human (head and neck and esophageal) tissue origin. Underlying mechanisms of flavopiridol-induced cell radiosensitivity may include inhibition of repair of DNA damage and cell cycle redistribution. Therefore, flavopiridol may have potential to improve the efficacy of radiotherapy. (Supported in part by CA 6492, Aventis Pharmaceuticals and MDACC MRP esophageal grant)

[Proc Amer Assoc Cancer Res, Volume 45, 2004]