We have proposed to study the mechanism of action of cis 1,2-diaminocyclohexyl malonato platinum (II) [(cisDACH)PT(mal)] and related compounds in the mouse L-1210 leukemia cell line. (cisDACH)Pt(mal) is a second generation platinum compound with comparable effectiveness to cis-diammino dichloro platinum (II) [cis(NH3)2Pt(Cl)2] but with better penetration of the blood brain barrier and reduced nephrotoxicity. It has already shown promise in some clinical trials. Our laboratories have recently developed new techniques to: 1) measure intracellular metabolites of (cisDACH)Pt(mal) and related platinum compounds; 2) measure platinum-DNA monoadducts, intrastrand G-G cross-links, and intrastrand G-X-G cross-links as well as interstrand cross-links; and 3) measure an excision nuclease activity capable of removing intrastrand cross-links. These techniques have not been previously available. We plan to use these techniques to answer the following questions: 1) What are the major metabolites of (cisDACH)Pt(mal) in the cell and are there significant differences between the metabolism of platinum compounds containing malonate and chloride leaving ligands? 2) What are the proportions of interand intrastrand cross-links in L-1210 cells treated with cytotoxic levels of (cisDACH)-Pt(mal) and related platinum compounds? 3) Do intrastrand cross-links correlate with the platinum induced inhibition of DNA synthesis and cytotoxicity? 4) How are intrastrand cross-links removed from the DNA of mammalian cells? and 5) What is the mechanism of resistance of the L-1210/DDP cell line to platinum (II) compounds and why is is not resistant to platinum compounds containing the DACH carrier ligand? In view of the current interest in (cisDACH)Pt(mal) and (transDACH)Pt(mal) as possible clinical drugs, the metabolic and mechanistic studies with (cisDACH)Pt(mal) should be particularly valuable at this time. In view of the widespread use of cis(NH3)2Pt(Cl)2 in the treatment of human cancers, the experiments designed to resolve the mechanism of DNA-platinum modification and repair are important. Finally, the studies with the resistant cell line of L-1210 may well serve as a model to facilitate the understanding of resistance to platinum drugs in human tumors.
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