Exploiting Novel Polyamine Regulatory Responses to a Therapeutic Advantage in Human Prostatic Carcinoma: A Preclinical Study
Abstract
We have previously reported that two polyamine antagonists currently undergoing clinical evaluation: the polyamine analog, N TO THE 11 to the 1, N TO THE 11-diethylnorspermine (DENSPM) and the biosynthetic enzyme inhibitor, 4-amidinoindan-l-one 2%- amidinohydrazone (CGP-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 other developments, we have determined that a polyamine analog related to DENSPM exerts meaningful antitumor activity against DU145 human prostate carcinoma xenografts and are seeking proof-of-principle for a novel polyamine gene-based antiproliferative strategy. The former will be optimized with respect to drug effects on polyamine regulatory responses and on the antitumor activity of the compound. More recently we have identified a novel targeting strategy involving inducible polyamine catabolism. The overall goal of both research efforts is to identify and develop polyamine-based I prostate-directed therapies as rapidly as possible.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2002
- Accession Number
- ADA405366
Entities
People
- Carl W. Porter
Organizations
- Health Research, Incorporated