Potential Test Systems for Chemotherapeutic Agents against Prostatic Cancer

5α-Reductase as a Target Enzyme for Anti-Prostatic Drugs in Organ Culture

“…In view of the central role played by 5a-reduction of T in the regulation of prostatic growth and physiology [1,22,24], a model system for testing drugs against cancer of the prostate, based on 5a-RA, has been developed and previously reported [8,19,21,25], This approach has been extended with the use of organ culture to an in vitro system, providing a more sensi tive and direct assay of the effects of agents on the target tissue, particularly human prostatic cancer. Short-term organ culture, as presently reported, provides a rapid and flexible tool for studying changes in biochemical parameters under various experimental conditions, while still maintaining nor mal morphological features of the intact tissue.…”

“…With respect to cancer of the prostate, one such compound is estracyt. It has been shown that one of the properties in its anti-androgenic action is an influence on 5 a-R A [7,8,19]. In vivo administration of estracyt to dogs and rats resulted in diminished 5a-RA of their prostates [8], H isaeter [7] reported no effect by estracyt on the rat ventral prostate after in vitro incubation or short-term (half-hour) in vivo adminis tration of the drug.…”

“…Since the 5a-reduction product of testosterone (T), dihydro testosterone (DHT), appears to be crucial for prostatic inte grity and function [1,22,24], a model system based on 5a-reductase enzyme activity (5a-RA) was developed in our laboratory for testing the action of chemotherapeutic agents potentially useful in prostatic cancer [8,19,21,25]. This approach involved in vivo administration of the drugs to test animals and subsequent in vitro assay of the enzyme activity in prostatic homogenates.…”

The Limitations of Model Systems in Prostatic Cancer

“…There are also significant differences in the sensitivities of hu man and animal tissues to cytotoxic drugs and extrapolations between species must be viewed with caution [11]. Examples of other problems include the facts that rats treated with chemotherapy lose significant amounts of weight [19] and mice have very low levels of complement which may make them a poor model for immunotherapy trials. In general, ani mals are poor models for hyperthermia because of different temperature regulating mechanisms [29], Because cures with chemotherapy are very rare and increased survival time is the reasonable expectation of successful che motherapy, animal model systems are handicapped by relati vely short life spans in which long term observations are im possible.…”

“…Neither of these variants closely mimics clinical prostatic cancer. The current use of non-neoplastic prostatic models has result ed in the selection of significant numbers of ''false positives", i.e., agents significantly affecting either DNA [21] or other synthetic processes [19] but relatively ineffective in man. Past experience has shown that relatively few patients with solid tumors respond to any one treatment strategy and, un less one is seeking a ''magic bullet", only modest responses to individualized treatment for individual tumors are the reason able expectation at this time.…”