Abstract
The relationship between DNA cross-linking and cell killing by cis-diamminedichloroplatinum(II) (cis-DDP) and l-phenylalanine mustard (L-PAM) was studied in L1210 cell culture lines and in mice bearing sensitive and resistant lines of L1210 leukemia. A line of L1210 mouse leukemia cells was developed which is resistant to cis-DDP in vitro. These cells, designated ZCR9, are cross-resistant to L-PAM. The effect of both drugs on the ZCR9 cells, compared to the parent L1210 K25 cells, was examined by DNA alkaline elution with and without the use of proteinase. The resistant line was similar to the normal line with regard to the kinetics of DNA cross-link formation and removal following treatment with cis-DDP or L-PAM. For both drugs, maximum cross-linking occurred after 6 hr; this is presumed to represent the time required for conversion of drug-DNA monoadducts to cross-links. In the resistant line, interstrand cross-linking by cis-DDP or L-PAM and DNA-protein cross-linking by cis-DDP were all reduced relative to the parent line. The interstrand cross-linking was reduced in approximately the same proportion as the cytotoxicity (in terms of dose modification factors). DNA-protein cross-linking by L-PAM, however, was similar in the two cell lines. The relationship between DNA cross-linking and cell killing by cis-DDP and L-PAM was also studied in mice bearing sensitive and resistant lines of L1210 leukemia. The cells were removed from untreated mice and tested in vitro for DNA cross-linking produced by the two drugs. Tumor sensitivity was assessed by comparing the survival of treated versus untreated mice which had been inoculated with the same cells used in cross-linking assays. A L1210 line which had been developed for resistance to cis-DDP exhibited marked reductions in both types of cross-linking by this drug when compared to its sensitive parent line. This line was not resistant to L-PAM and exhibited no significant depression in cross-linking by this drug. A second line, made resistant to L-PAM, showed marked reductions in L-PAM-induced cross-linking compared to its parent line. This line was cross-resistant to cis-DDP but showed only a modest reduction in cis-DDP-induced cross-linking. Thus, in three of the four cell-drug comparisons, DNA cross-linking and in vivo cell killing were well correlated. The reason for the deviation of the fourth case was investigated in preliminary studies, but no definitive answer was obtained. The results suggest that DNA cross-linking correlates with tumor sensitivity to bifunctional agents.
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