Binding Characteristics of (–)‐(R)‐2‐Aminomethylpyrrolidine(1,1‐cyclobutanedi‐carboxylato)‐2‐platinum(II) to DNA, RNA and Protein Molecules in HeLa Cells and Its Lethal Effect: Comparison with cis‐ and trans‐Diammmedichloroplatinums(II)

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Abstract
HeLa S‐3 cells were treated with 195mPt‐radiolabeled (–)‐(R)‐2‐aminomethylpyrrolidine(1,1‐cyclobutanedicarboxylato)‐2‐platinum(II) (DWA2114R) under various conditions, and the relationship between the lethal effect of the agent and the number of platinum (Pt) atoms binding to DNA, RNA and proteins was examined. The values of mean lethal concentration for the cells treated with DWA2114 at 37°C for 1, 2 and 3 h were 137.3, 75.10 and 51.17 μM, respectively. Cells were treated identically and the numbers of Pt atoms combined with DNA, RNA and protein molecules were determined after fractionation of the cells. In this way, the D0 values (D0, dose that would give an average of one lethal event per member of the population), expressed as the drug concentration, were substituted for the number of Pt atoms combined with each fraction. The target volumes, the efficacy of Pt atom to kill cells expressed as the reciprocals of the D0 values, were then calculated for each fraction. Our findings suggested that DNA was the primary target molecule for cell killing by DWA‐2114R. The target volumes for DNA were 3.36 × 104, 4.00 × 104 and 4.10 × 104 nucleotides for 1‐, 2‐and 3‐h treated cells, respectively. The cell‐killing effects of DWA2114R were lower than those of cis‐dianuninedichloroplatinum(II) (CDDP) by factors of 1.54, 1.42 and 2.51 for 1‐, 2‐ and 3‐h treatments at 37°C, respectively, in terms of the target volume, while those in terms of the mean lethal dose (D0) were 14.8, 11.2 and 16.0, respectively. The efficacy of DWA2114R in killing the cells was 2.6 times greater than that of CDDP in the 3‐h treatment at 0°C.

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