RELATIONSHIP BETWEEN CELL-KILLING EFFICIENCY AND NUMBER OF PLATINUM ATOMS BINDING TO DNA, RNA, AND PROTEIN MOLECULES IN HELA-CELLS TREATED WITH CIS-DIAMINE(GLYCOLATO)PLATINUM(II)

HeLa S-3 cells were treated with Pt-195m-radiolabeled cis-diamine(glyc olato)platinum(II) (254-S) under various conditions, and the relations hip between the lethal effect and the numbers of Pt atoms binding to D NA, RNA, and proteins was examined. The mean lethal concentrations for the cells treated with 254-S at 37 degrees C for 0.5, 1, 2, and 3 h w ere 67.1, 47.0, 26.8 and 8.1 mu M, respectively. Using identically tre ated cells, we determined the numbers of Pt atoms combined with DNA, R NA, and protein molecules after fractionation of the cells. In this wa y, the D-0 values (D-0, the dose that causes an average of one lethal event per member of the population), expressed as the drug concentrati on, could be related to the number of Pt atoms combined with each frac tion. The efficiency of the Pt atom in killing the cells, expressed as the reciprocal of the D-0 values, was then calculated for each fracti on. The results suggested that DNA was the primary target for cell kil ling by 254-S, The target volumes for DNA were 3.96, 4.97, and 11.77 x 10(4) nucleotides for 1-, 2-, and 3-h treated cells, respectively. In terms of the target volume, the cell-killing effects of 254-S were co mparable to those of cis-diamine-dichloroplatinum(II) (CDDP), for whic h the target volumes under identical conditions were determined to be 5.17, 5.71, and 10.3 x 10(4) nucleotides, respectively, while in terms of the mean lethal dose (De), the cell-killing effects of 254-S were lower than those of CDDP by a factor of 5.1 (47.0/9.3), 4.0 (26.8/6.7) , or 2.5 (8.1/3.2) for 1-, 2-, or 3-h treatment, respectively.