Targeting apoptosis by hydroxymethylacylfulvene in combination with gamma radiation in prostate tumor cells

Hydroxymethylacylfulvene (HMAF) is a novel agent with alkylating activity a nd is a potent inducer of apoptosis that is currently undergoing Phase II c linical trials for prostate cancer. This study explored the pro-apoptosis a nd anti-proliferative potential of HMAF in combination with gamma radiation in human prostate tumor cell lines. Apoptosis was assessed based on the ge neration of fragmented DNA, a terminal transferase dow cytometry assay, and cell morphology. In each of the tumor cell lines examined, radiation alone induced a marginal level of apoptosis, even after a prolonged 48-h incubat ion after exposure. In contrast, HMAF alone was a potent inducer of apoptos is in prostate tumor cells but not in normal cells. Marked levels of apopto sis in tumor cells were also observed for the combination of HMAF with gamm a radiation. When drug treatment preceded irradiation, at least additive le vels of apoptosis were observed in both androgen-responsive and androgen-in dependent cells. The combined treatment with ionizing radiation and HMAF re duced the radiation dose needed for the same level of clonogenic survival u p to 2.5-fold. The potentiation of apoptosis and reduction in the clonogeni c survival of tumor cells occurred at HMAF concentrations lower than that w hich reduced survival to 10% and at doses up to 6 Gy. No potentiation of ap optosis or clonogenic inhibition was noted in normal cells. These results s uggest that the combination of HMAF with gamma radiation may have clinical utility for treatments of prostate cancer. (C) 2000 by Radiation Research s ociety.