Toxicity of cisplatin and hydroxymalonatodiammine platinum (II) towards mouse bone marrow and B16 melanoma in relation to DNA binding in vivo.

The antitumour selectivity of cisplatin and hydroxymalonatodiammine platinum II (Pt[OHmal(NH3)2]), a second generation platinum drug, was evaluated in C57B1/Cbi mice bearing advanced intramuscular B16 melanoma. At maximally tolerated doses, Pt[OHmal(NH3)2] produced greater inhibition of growth of the advanced B16 melanoma than did cisplatin. Comparison of dose-response curves for survival of B16 lung colony-forming cells and bone marrow stem cells treated in vivo indicated that selective killing of B16 cells was achieved with Pt[OHmal(NH3)2], whereas cisplatin was relatively nonselective. The extent of reaction of platinum with DNA at doses producing measurable levels of survival in tumour and marrow in vivo was similar to values previously observed in cultured cells treated with cisplatin in vitro. Studies of the amount of platinum bound to DNA in tumour and marrow following administration of the two drugs revealed that the improved selectivity of Pt[OHmal(NH3)2] was associated with a selective increase in the amount of platinum bound to tumour DNA, relative to cisplatin. In addition, platinum lesions produced in DNA by Pt[OHmal(NH3)2] appeared to be more effective in producing tumour cell killing than those produced by cisplatin. No significant excision of total DNA-bound platinum from tumour was observed up to 48 h after administration of either drug.