CYTOTOXICITY AND CELLULAR ACCUMULATION OF A NEW CIS DIAMMINEPLATINUM(II) COMPLEX CONTAINING PROCAINE IN MURINE L1210 CELLS SENSITIVE AND RESISTANT TO CIS-DIAMMINEDICHLOROPLATINUM(II)

The emergence of drug resistance during tumor chemotherapy is one of t he main problems associated with cancer treatment, particularly with c isplatin (cis-DDP). In the hope of overcoming this problem, various ci s-DDP-derived compounds have been synthesized, and their pharmacologic al activity was compared with that of cis-DDP. In this paper we report on studies on the cytotoxic activity induced by minechloro-[2-(diethy lamino)ethyl-4-aminobenzoate, N-4]-chlorideplatinum(II) monohydrochlor ide monohydrate (DPR), a new complex of platinum containing procaine. All experiments were carried out on murine leukemic cells, which were either sensitive (L1210) or resistant (L1210/DDP) to cis-DDP. A tetraz olium dye (MTT) assay conducted 5 days after a 2-h exposure of cells t o both drugs was utilized to determine the resistance factor (RF) of L 1210/DDP cells as compared with the sensitive wild-type cells. Drug ac cumulation and efflux, together with the amount of platinum bound to D NA, were also investigated. The activity of DPR on sensitive cells was not significantly different from that of cis-DDP. Conversely, DPR was 4.3 times more effective than cis-DDP on resistant cells. A decreased drug accumulation is one of the mechanisms of resistance to cis-DDP o f L1210/DDP cells. However, DPR accumulation was not significantly dif ferent in sensitive and resistant L1210 cells. Under culture condition s that yielded similar intracellular platinum concentrations, treatmen t with DPR produced significantly greater DNA platination than did tre atment with cis-DDP in both cell lines. No difference in efflux was ob served between L1210 and L1210/DDP cells exposed to either cis-DDP or DPR. Our results show that in parental cells, DPR is as potent as cis- DDP on a molar basis, and it is also minimally cross-resistant with ci s-DDP in L1210/DDP cells. A direct implication of our results is that DPR could be useful in those human tumors showing a mechanism of resis tance similar to that of L1210/DDP cells.