ENHANCED LEVELS OF CYCLIC-AMP, ADENOSINE(5')TETRAPHOSPHO(5')ADENOSINE AND NUCLEOSIDE 5'-TRIPHOSPHATES IN MOUSE LEUKEMIA P388/D1 AFTER TREATMENT WITH CIS-DIAMMINEDICHLOROPLATINUM(II)

As part of the exploration of the mechanism of platinum(II) complex-induced growth inhibition and/or cytotoxicity, we studied the intracellular levels of several nucleotides during treatment of mouse leukemia P388/D1 at selected concentrations of 1-mu-M cis-diamminedichloroplatinum(II) (cis-DDP) and 20-mu-M of its trans-isomer (trans-DDP). The effects and their time-dependences are correlated with those on cell growth parameters previously published (Just G and Holler E, Cancer Res 49: 7072-7078, 1989). The effects of cis-DDP are strong and irreversible, whereas those of trans-DDP are marginal and reversible, in parallel with similar effects on cell growth parameters. Concentrations of nucleoside 5'-di and 5'-triphosphates increase in parallel with cellular DNA and protein content by three- to four-fold after 60 hr of treatment. The nucleoside monophosphates dAMP, dGMP and dTMP reveal concentration maxima during exponential cell growth that are two- to six-fold higher than in the control cultures. Levels of cyclic AMP, adenosine(5')tetraphospho(5')adenosine (Ap4A) and CDP rise three- to five-fold above those in the control cultures within a few hours of the start of treatment. The level of coenzyme NAD+ falls below that of the control, concomitantly with an arrest of cells in the G2 phase of the cell cycle and with the appearance of giant cells. Due to the high reactivity of cis-DDP and the continuous concentration increase during the treatment, purine nucleoside 5'-triphosphates provide a possibility for the acquisition of resistance to cis-DDP. The correlation of responses of metabolically and regulatory active nucleotides with biological effects suggests their function in antitumorigenesis.