Effect of thiourea on survival and DNA cross-link formation in cells treated with platinum(II) complexes, L-phenylalanine mustard, and bis(2-chloroethyl)methylamine.

This study examines the mechanisms by which thioumeamay protect cells against toxic actions produced by platinum com plexes or nitrogen mustards. Mouse leukemia Li 210 cells were assayed for survival by colony formation in soft agamand for DNA interstrand cross-linking using the alkaline elution method. The survival of Li 2i 0 cells treated with cis-and trans Pt(Il)diamminedichloride was enhanced by posttreatment in cubation with thiourea. This enhancement was lost over a period of 6 to 12 hr after drug exposure, suggesting that the cytotoxicity resultedfrom a delayedeffect which was suscep tible to blockade by thiourea. DNA lnterstrand cross-link formation was prevented when thiourea was added immediately after cis-Pt(ll)diammine dichloride treatment but was not reversed once cross-links had formed. Survival enhancement and cross-link prevention by thiourea depended in a similar manner on thiourea concentra tion and on the interval between platinum treatment and thi ourea addition. Cytotoxicity by nitrogen mustar,ds was also prevented by thiourea, but this protectability was lost much more rapidly than in the case of Pt(ll) complexes. In contrast to cis-Pt(ll)diamminedichloride, delayed intemstmand cross-link for mation by L-phenylalanine mustard was not prevented by thi ourea. The results suggest that thioumeacan react with cis-Pt(ll) DNA monoadducts to prevent their conversion to potentially lethal cross-links. Thiourea may also react with nitrogen mus tards as well as Pt(ll) complexes to directly inactivate free drug.