EFFICACY OF THE PLATINUM ANALOG (PT(CIS-DACH)(DPPE)-2NO(3)) ON HISTOCULTURED HUMAN PATIENT BLADDER-TUMORS AND CANCER CELL-LINES

Cisplatinum is currently used as a front line agent in many important tumors, but its dose-limiting nephrotoxicity prevents potential effica cy. There is therefore great interest in developing new platinum agent s that have less toxicity. We have synthesized new platinum analogues containing DACH as a cancer ligand and DPPE as a leaving group. Previo usly we showed that these new platinum complexes have much less nephro toxicity than cisplatinum. In thepresent study, the efficacy of one ne w platinum complex was evaluated with human patient bladder tumor spec imens in three-dimensional histoculture as well as with monolayer cult ures of cancer cell lines. The efficacy end points wed were glucose co nsumption and thymidine incorporation on the histocultured specimens a nd MTT reduction on monolayer cell cultures. Our results showed that t he new platinum complex was more effective at high concentration (10(- 3) M) but less effective at low concentration (10(-4) M) compared to c isplatinum on histocultured bladder tumor specimens. The compound demo nstrated higher efficacy than cisplatinum on P-388, and L-1210 leukemi c cell lines. The new analog demonstrated similar efficacy to cisplati num on the MKN-45 human stomach cancer cell line. The PC-14 human lung cancer cell line, MH(1)C(1) rat hepatoma cell line, NIH-OV3, SKOV-3 o varian cancer cell lines were as sensitive to the new analog as to cis platinurn at high concentrations of the new platinum analogue. The cis platinum-resistant M-14 melanoma cell line was not sensitive to either the new analog or cisplatinum. Based on these results, this novel pla tinum compound appears to be a valuable lead compound with high effica cy and low nephrotoxicity.