Seven independent research programs are interacting in a concerted effort to identify inhibitors of polyamine biosynthesis and/or function as potential antic-cancer agents with the ultimate coal of utilizing those agents to improve the treatment and curability of human cancer. The impetus for this study derives, in part, from the dependence of neoplastic cell growth on sustained polyamine biosynthesis and the increased rate of this activity in neoplastic cells relative to their normal counterparts. Agents being synthesized by three chemistry programs include: polyamine analogs and conjugates (Dr. R. Bergeron, U. of Florida, Gainesville), inhibitors of spermidine and spermine synthases and the processing of S-adenosylmethionine (AdoMet metabolism (Dr. J. Sufrin, Roswell Park Memorial Institute, Buffalo, NY). These and compounds derived from outside sources are being tested for biochemical effects on polyamine biosynthesis and molecular biology (Dr. A. Pegg, Penn. State University, Hershey, PA), for cellular effects and antiproliferative activity in the in vitro and in vivo (Dr. C. Porter, P.I.), for drug interaction studies with DNA and DNA-reactive antineoplastics (Drs. L. Marton and D. Deen, U. California, San Francisco), and for drug effects on human lung carcinoma growth in vitro and in vivo (Drs. R. Casero and S. Baylin, Johns Hopkins, Baltimore, MD). Compounds currently being studied within the various programs include: AdoDATO and AdoDATAD, inhibitors, respectively, of spermidine and spermine synthase; AdoMet analog inhibitors of AdoMet decarboxylase; DFMO and related inhibitors of ornithine decarboxylase; bisalkyl analogs of spermidine and spermine; analogs of 5'-deoxy-5-methylthioadenosine and others. Data generated by the various biological evaluation programs provides continual feedback information for the design and synthesis of additional compounds. While it is the primary goal of this group effort to identify new and practical anticancer treatments, information relevant to the role and function that poyamines fulfill in cell proliferation will also be sought, thus enhancing our understanding of the neoplastic process in general.
Showing the most recent 10 out of 121 publications
