DF/HCC Program Affiliation

Cancer Cell Biology
Translational Pharmacology and Early Therapeutic Trials

Research Abstract

My research interests have been twofold twofold: (1) the design, synthesis, and in vitro/in vivo evaluation of novel inhibitors of folate metabolism as potential anticancer drugs; and (2) the design and synthesis of lipophilic nonclassical antifolates as potential drugs against opportunistic pathogens in AIDS patients or cancer patients treated with immunosuppresive cytototoxic drugs. The principal target enzyme for both projects is dihydrofolate reductase (DHFR), although in some of our earlier work other enzymes of de novo purine and pyrimidine biosynthesis, such as thymidylate synthase (TS), and glycinamide ribonucleotide formyltransferase (GARFT), have also been targeted. Organisms potentially amenable to treatment with lipophilic DHFR inhibitors include Pneumocystis carinii, Toxoplasma gondii, Cryptosporidium parvum, and Mycobacterium avium complex. In some instances, lipophilic DHFR inhibitors are also potentially useful as anticancer drugs. A promising new compound developed in this program is talotrexin (PT523), which was among the first drugs accepted for pre-clinical development by the RAID program of the National Cancer Institute. Talotrexin is approximately tenfold more potent than methotrexate as a DHFR inhibitor, is taken up by cells by the same concentrative transport system but with approximately tenfold greater efficiency, shows activity against a variety of methotrexate-resistant cell lines in the laboratory. An industry-sponsored multi-institutional Phase I/II trials of talotrexexin against non-small cell lung carcinoma (NSCLC) have given promising results and were presented at the most recent AACR-EORTC meeting in Philadelphia. Other clinical studies are in progress or planned..

Publications

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