This is revised submission requesting renewal funds for an ongoing project in anticancer drug development. It is focused on the use of gadolinium(III) texaphyrin cores as carriers to bring Pt agents directly to tumor sites. Gadolinium(III) texaphyrins are a class of expanded porphyrins developed by the P.I. that have a clinically validated ability to localize selectively in tumors. By conjugating a Pt anticancer agent to texaphyrin and controlling the nature of the platinum species employed, we expect to produce new drug leads that i) provide for an increased intracellular delivery of platinum, ii) circumvent DNA repair mechanisms, and iii) enhance wild- type p53 function, thus overcoming three key determinants of cisplatin resistance. We now have in hand a lead texaphyrin-platinum agent (conjugate 3) that shows no resistance between ovarian A2780 and its isogenic platinum resistant partner (2780CP) in cell culture. We have also completed an in vivo, multidose toxicity study of this lead system and have confirmed that, relative to analogous FDA-approved Pt agents, it is capable of delivering approximately twice the dose of Pt to balb/c mice without engendering toxic symptoms. To develop this project further we will pursue the following specific aims: 1) Study the in vitro properties of our lead system, conjugate 3;2) carry out in vivo efficacy studies of this lead system and new agents we prepare;3) determine toxicity, drug distribution;quantify the ability of promising conjugates to localize within the tumor and form Pt DNA adducts, and 4) synthesize new conjugates, including those based on Pt(IV) centers. The net result of this effort will be one or more agents in advanced preclinical testing that addresses the all- important problem of platinum drug resistance.
This ongoing project involves the synthesis and study of small molecule systems that carry platinum-type anticancer agents directly to the tumor. This is expected to limit the toxic side effects and increase efficacy. This approach looks particularly promising for the treatment of Pt-resistant ovarian cancer.
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