The interactions between bioinorganic metal compounds (platinum-based, gallium-based, cadmium-based, etc.) and cellular DNA, cellular proteins, etc., are assessed, with a focus on modulating the potential cytotoxic activity of these agents. Studies conducted within the time frame of this report show that: 1) Platinum cytotoxicity can be modulated by pharmacologic doses of paclitaxel, IL1-alpha, or TNF, in tissue culture and in animal models. In the case of paclitaxel, this effect is also apparent in the clinic. The mechanism of these effects appears to be modulation of one or more of the subcellular pharmacologic parameters of platinum handling. 2) When analysed by DNA damage level (lesions per kb of DNA), there is marked similarity between cell lines and clinical studies in the relationship(s) between DNA damage and cytotoxic effect. For example, the platinum-DNA damage level of >0.060 lesions/kb is very difficult to obtain clinically. In tissue culture, this is the level of DNA damage required to kill mesothelioma cells, platinum-resistant ovarian cancer cells, and other platinum-resistant cell lines. In the clinic, the inability to achieve objective response in these tumors, is correlated with the inability to clinically achieve levels >0.060 lesions/kb. 3) Preliminary studies suggest that cadmium is a potentially clinically exploitable heavy metal. It's ability to kill cancer cells in tissue culture, occurs at levels that are well tolerated in animals.
