Inhibition of nucleic acid synthesis in P388 lymphocytic leukemia cells in culture by cis-platinum derivatives.
Cis-diaminedichloroplatinum(II) [cDDP] and three related derivatives Pt(mal)(NH3)2, PtCl2(dach) and Pt(mal) (dach) have been observed to possess cytotoxicity against the growth of P388 lymphocytic leukemia cells. DNA synthesis in P388 cells was inhibited by the agents in a manner which was consistent with their ED50 values for cytotoxicity. When P388 cells were treated with these platinum complexes in vitro at doses which caused more than 80% inhibition of DNA synthesis, no significant inhibition was observed for thymidine, kinase, thymidine monophosphate kinase, carbamoyl phosphate synthetase, or aspartate transcarbamoylase activities. Thus, there was no evidence that these agents inhibited de novo purine, pyrmidine, or deoxynucleotide synthesis. All of the agents did inhibit the nuclear DNA polymerase activity, but the extent of inhibition was 20% or less at doses which caused greater than 70% inhibition of DNA synthesis. Thus, the inhibition of DNA synthesis appeared to be due to cisplatinum(II) drug binding to the DNA bases. This was estimated to be 1 atom of platinum per 1500-3000 DNA base pairs which is consistent with other studies. The platinum complexes with chloro leaving ligands caused considerable DNA strand scission by 24 h at 10 times the ED50 dose, most likely a measure of impending cell death. In contrast, the platinum complexes with malonato leaving ligands did not cause significant strand scission by 24 h at similar doses. They also exhibited a significant delay in the inhibition of DNA synthesis. These data were interpreted as resulting from slower monoadduct to diadduct conversion, but it is not possible to eliminate the possibility of a different mode of interaction with DNA or a different mechanism of cytotoxicity for the malonato compounds.
Oswald
C B
CB
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Chaney
S G
SG
Hall
I H
IH
D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D012313:RNA / Q000096:biosynthesis*; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
D019384:Nucleic Acid Synthesis Inhibitors; D012313:RNA; D004247:DNA; D001221:Aspartate Carbamoyltransferase; D013937:Thymidine Kinase; D002945:Cisplatin