Exploiting Novel Polyamine Regulatory Responses to a Therapeutic Advantage in Human Prostatic Carcinoma: A Preclinical Study (Prostate)
Abstract
We have previously reported that two polyamine antagonists currently undergoing clinical evaluation: the polyamine analog, N(1), N(11)-diethylnorspennine (DENSPM) and the biosynthetic enzyme inhibitor, 4-amidinoindan-l-one 2'- amidinohydrazone (COP-48664), appear to exert unusual regulatory effects in prostate carcinoma cell lines relative to other cell lines. We have proposed to develop strategies in vitro and in vivo for therapeutically exploiting this observation. In pursuit of this goal, we have discovered that CGP-48664 potently induces apoptosis via a p53 / caspase-3 dependent pathway that is unrelated to its intended mode of action as an inhibitor of polyamine biosynthesis. Such an effect has not been previously reported and may have relevance to ongoing clinical trials with the compound. Future studies will investigate the therapeutic significance of this finding in vivo. In another development, we have determined that a polyamine analog related to DENSPM exerts meaningful antitumor activity against DUl45 human prostate carcinoma xenografts. This finding will be optimized with respect to drug effects on polyamine regulatory responses and on the antitumor activity of the compound. The overall goal of both research efforts is to identify and develop relevant prostate-directed therapies as rapidly as possible.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1999
- Accession Number
- ADB262549
Entities
People
- Carl Porter
Organizations
- Roswell Park Comprehensive Cancer Center