Publishing ID: 4986
Targeting Apoptosis by Hydroxymethylacylfulvene in Combination with g-Radiation in Prostate Tumor Cells.
Barbara A Woynarowska, Kari Roberts, Jan M Woynarowski, Terence S Herman, John R MacDonald, Univ of Texas Health Sci Ctr, San Antonio, TX; Cancer Therapy and Res Ctr, San Antonio, TX; MGI Pharma, Inc, Bloomington, MN.
Hydroxymethylacylfulvene (HMAF, MGI 114, irofulven) is a novel agent with alkylating activity and a potent inducer of apoptosis, currently undergoing Phase II trials for several solid tumor types including prostate cancer. This study explored pro-apoptotic and antiproliferative potential of HMAF in combination with g-radiation in human prostate tumor cell lines. In each of the tumor cell lines examined (LNCaP-Pro5, LNCaP-LN3, and PC-3) g-radiation alone (doses of 6-8 Gy) induced marginal apoptosis, even after a prolonged 48 h post-exposure incubation. In contrast, HMAF alone (at 1-5 æM) was a potent inducer of apoptosis in prostate tumor cells but not in normal cells (NCM 460). Profound apoptosis induction in tumor cells was retained by the combination of HMAF with g-radiation. When drug treatment preceded irradiation, at least additive apoptosis was observed in both androgen-responsive and in androgen-independent cells. Compared to radiation alone, the combined treatment of ionizing radiation with HMAF reduced, up to 2.5 fold, the radiation dose needed for the same level of clonogenic survival measured by colony formation. The potentiation of apoptosis and reduction in clonogenic survival of tumor cell lines occurred at HMAF concentrations of 1.3-3.9 æM (lower than the respective D10 values for HMAF alone) and at low radiation doses of up to 6 Gy. No potentiation of apoptosis or clonogenic inhibition was noted in normal NCM 460 cells. Overall, these results suggest that the combination of HMAF with g-radiation may have potential clinical utility for the treatment of prostate cancer. (Supported by NCI Grant CA78706 and MGI Pharma, Inc.) |
