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Approaches to prostatic cancer chemotherapy using the Dunning R3327H prostatic adenocarcinoma
Abstract:
Androgen-responsive cells: To determine if testosterone or dihydrotestosterone is the main trophic hormone of prostatic adenocarcinoma, we have treated Dunning R3327H prostatic adenocarcinoma-bearing rats with 6-methylene progesterone, which blocks conversion of testosterone to dihydrotestosterone. Copenhagen-Fisher rats were treated with steroid (20 mg/Kg daily) immediately following implantation of tumor and thereafter for 117 days. There was a 92% inhibition of growth of tumors and a lesser effect upon prostate and seminal vesicles. Tumor-free body weights remained unchanged. Both treated and untreated tumors had equivalent DNA content on a per weight basis. This result supports the thesis that prostatic adenocarcinoma requires dihydrotestosterone for growth. Androgen-insensitive cells: Advanced prostate cancer does not respond to endocrine therapy but is temporarily controlled by the cytotoxic steroid estramustine. The latter shows significant selective binding to prostatic protein. To develop chemotherapeutic agents that will control androgen-insensitive cells and possess improved selectivity for prostatic protein, we have studied a number of steroids for their ability to displace 3H-labeled estramustine from prostatic cytosolic proteins. Surprisingly, a carbamido substituent at the C17 position was found to confer significant binding affinity for prostatic estramustine-binding protein. Extension of this structural characteristic to the estramustine type of molecule is being studied.
Insights
Dihydrotestosterone is essential for prostate adenocarcinoma growth, as blocking its production inhibited tumor growth by 92%. New chemotherapeutic agents targeting androgen-insensitive prostate cancer show promise, with carbamido substituents enhancing binding affinity.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Prostatic adenocarcinoma growth is androgen-dependent, primarily mediated by dihydrotestosterone.
- Advanced prostate cancer often becomes androgen-insensitive and resistant to endocrine therapy.
- Estramustine is a cytotoxic steroid that selectively binds to prostatic proteins, offering temporary control of advanced prostate cancer.
Purpose of the Study:
- To investigate whether testosterone or dihydrotestosterone is the primary trophic hormone for prostatic adenocarcinoma.
- To develop novel chemotherapeutic agents targeting androgen-insensitive prostate cancer cells with improved selectivity for prostatic proteins.
Main Methods:
- Rats bearing Dunning R3327H prostatic adenocarcinoma were treated with 6-methylene progesterone to block testosterone to dihydrotestosterone conversion.
- Steroid treatments were administered daily for 117 days.
- Various steroids were studied for their ability to displace 3H-labeled estramustine from prostatic cytosolic proteins to assess binding affinity.
Main Results:
- Treatment with 6-methylene progesterone resulted in a 92% inhibition of tumor growth, with lesser effects on prostate and seminal vesicles.
- Tumor-free body weights remained unchanged, and DNA content per weight was equivalent between treated and untreated tumors.
- A carbamido substituent at the C17 position was found to significantly enhance binding affinity for the prostatic estramustine-binding protein.
Conclusions:
- Dihydrotestosterone is the principal trophic hormone required for the growth of prostatic adenocarcinoma.
- Structural modifications, such as carbamido substituents, show potential for developing more effective chemotherapeutic agents against androgen-insensitive prostate cancer.