CANCER CHEMOTHERAPEUTIC AGENTS;CARRIER MOLECULES FOR CISPLATIN In the past few years, peripheral-type benzodiazepine receptors (PBZR) have been identified - initially as binding sites in peripheral tissues - with a noticeably different spectrum of drug activity than that of the more celebrated central-type receptor ligands (e.g. Valium. It has been found that the density of these receptors is increased both in ovarian carcinomas (as compared with benign ovarian tumors and with normal ovaries), and in human gliomas. This property has been used for PET imaging of human brain tumors using 11C radiolabelled, selective peripheral legends. It has been shown that the peripherally active ligands inhibited the growth of human melanoma cells and were able to potentiate the antiproliferative activity of recombinant human interferons. The initial aim of this proposal is to tests the hypothesis that PBZR ligands can be used, not only as anti-cancer agents in their own right, but as carrier moleculs to target cancerous organs (high PBZR density) with known chemotherapeutic agents which have limited utility due to poor tissue distribution (e.g. cisplatin). The achievement of this goal requires the synthesis and biological evaluation of chelates of platinum with PBZR ligands. Initially, it is intended to use a 5-(2-pyridyl) substituted-1,4-benzodiazepine as the substrate for chelation with the platinum reagent. This should demonstrate the viability of the proposal, although other, structurally different PBZR ligands, can be envisaged as agents for chelation with, perhaps, differing bioavailabilities. Initial testing will be carried out by our collaborators at the NIH. Ligands that are active at the PBZR will be submitted to the Fox-Chase Cancer institute for cytotoxicity evaluation an to the NCI for subsequent in vivo evaluation.
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