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Effect of Thiourea on Survival and DNA Cross-Link Formation in Cells Treated with Platinum(II) Complexes, L-Phenylalanine Mustard, and Bis(2-chloroethyl)methylamine¹

Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

This study examines the mechanisms by which thiourea may protect cells against toxic actions produced by platinum complexes or nitrogen mustards. Mouse leukemia L1210 cells were assayed for survival by colony formation in soft agar and for DNA interstrand cross-linking using the alkaline elution method.

The survival of L1210 cells treated with cis- and trans-Pt(II)diamminedichloride was enhanced by posttreatment incubation with thiourea. This enhancement was lost over a period of 6 to 12 hr after drug exposure, suggesting that the cytotoxicity resulted from a delayed effect which was susceptible to blockade by thiourea.

DNA interstrand cross-link formation was prevented when thiourea was added immediately after cis-Pt(II)diamminedichloride 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 concentration and on the interval between platinum treatment and thiourea addition. Cytotoxicity by nitrogen mustards was also prevented by thiourea, but this protectability was lost much more rapidly than in the case of Pt(II) complexes. In contrast to cis-Pt(II)diamminedichloride, delayed interstrand cross-link formation by L-phenylalanine mustard was not prevented by thiourea.

The results suggest that thiourea can react with cis-Pt(II)-DNA monoadducts to prevent their conversion to potentially lethal cross-links. Thiourea may also react with nitrogen mustards as well as Pt(II) complexes to directly inactivate free drug.

¹ A portion of this work has appeared in abstract form (29).

² Visting Scientist, Laboratory of Molecular Pharmacology.

Received 5/29/79. Accepted 9/13/79.