Protection of human tumor cells of differing radiosensitivity by WR-1065

We examined the ability of WR-1065, the biologically active aminothiol form of the clinically used drug amifostine (WR-2721, Ethyol(R)), to protect cu ltures of two human glioblastoma cell lines of greatly differing radiosensi tivity from the cytotoxic effects of gamma radiation. M059J cells are extre mely radiosensitive compared to M059K cells (which were derived from the sa me tumor) and are defective in the DNA-dependent protein kinase (DNAPK)-med iated pathway for the repair of DSBs. In spite of their marked phenotypic d ifferences, the two glioblastoma lines were protected equivalently (similar to 1.8-fold) after a 30-min preirradiation treatment with 4 mM WR-1065. Th ese findings are in agreement with earlier studies that showed no relations hip between the ability of another aminothiol, cysteamine, to protect human tumor cells with differing abilities to repair DSBs and/or radiosensitivit y. Thus it appears that differences in intrinsic radiosensitivity and abili ty to repair DSBs are not important general factors in the modulation of th e radiosensitivity of human cells by aminothiols. Because of a previous rep ort that the radiosensitive mutant rodent xrs5 cell line (which, like M059J , is defective in the DNAPK-mediated pathway for repairing DSBs) is unusual ly refractory to the radioprotective effects of WR-1065, we re-examined the ability of WR-1065 to protect these cells. In contrast to the earlier stud ies, both the wild-type and mutant rodent lines were protected extensively by WR-1065. This discrepancy might be related to some unknown factor, such as differences in chromatin organization among xrs5 subclones that arise du ring their karyotypic evolution, possibly leading to altered DNA-drug assoc iations. (C) 2000 by Radiation Research Society.