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Biomedical subjects

P Rennie

Publications and source records attributed to P Rennie.

13 recordsLinked to original sources
PubMed1998

Intermittent androgen suppression for prostate cancer: rationale and clinical experience.

The rationale behind intermittent androgen suppression (IAS) is based on: (1) observations that androgen ablation is palliative, not curative, in most patients with prostate cancer, and that quality of life must be considered; (2) the assumption that immediate androgen ablation is superior to delayed therapy in improving survival; (3) the hypothesis that if tumour cells surviving androgen withdrawal are forced into a normal pathway of differentiation by androgen replacement, then apoptotic potential might be restored and progression to androgen independence delayed. Several centres have now tested the feasibility of IAS therapy in non-randomized groups of prostate cancer patients using serum of prostate-specific antigen levels as trigger points. Clinical data suggest that prostate cancer is amenable to control by IAS and offers clinicians an opportunity to improve patients' quality of life by balancing the benefits of immediate androgen ablation (delayed progression and prolonged survival) while reducing treatment-related side effects and expense. Whether time to progression and survival is affected in a beneficial or adverse way is being studied in randomized, prospective protocols.

Androgen Antagonists↗
PubMed1993

Substitution of valine-865 by methionine or leucine in the human androgen receptor causes complete or partial androgen insensitivity, respectively with distinct androgen receptor phenotypes.

We have identified two different single nucleotide missense substitutions at valine-865 in exon 7 of the human androgen receptor (AR) gene in two families with androgen resistance. Val-->methionine is associated with the complete syndrome; Val-->leucine is associated with the partial form. In genital skin fibroblasts, both alterations yield a normal maximum binding capacity, but an increased apparent equilibrium dissociation constant for all androgens tested. In genital skin fibroblasts, Val865-Met A-R complexes have increased rate constants of dissociation with 5 alpha-dihydrotestosterone, and the nonmetabolized ligands methyltrienolone or mibolerone (MB); their Val865-Leu counterparts have increased rates with methyltrienolone and MB, but not with 5 alpha-dihydrotestosterone. In transiently transfected COS-1 or PC-3 cells, Met865 AR is more severely impaired than Leu865 AR in transactivating two different androgen-responsive reporter constructs, thereby correlating with clinical phenotype. In COS-1 cells exposed to MB for 74 h, this relative impairment correlates with the relative instability of the MB-binding activity of each mutant AR, suggesting that their respective intrinsic transcriptional regulatory competence is normal. Notably, these mutant ARs lose significantly more MB-binding activity than immunoreactivity, suggesting that prolonged MB exposure induces them to adopt a nonbinding state. The position homologous to Val865 in the AR is occupied by Leu or Met in the three steroid receptors closely related to the AR. This indicates the structural subtlety that underlies the steroid-binding activity of different steroid receptors.

Amino Acid Sequence↗
PubMed1979

Androgen receptors in benign and malignant prostatic tissue.

A new procedure has been developed to purify prostatic cell nuclei and to achieve a high yield of nuclear material for study. This technique allowed the investigation of the enzyme 5-alpha-reductase and its relationship to the translocation of dihydrotestosterone and androgen receptors into the nucleus of the prostatic cell. The studies revealed that 5-alpha-reductase was localized chiefly to the stromal components of all types of prostatic tissue. Although there is a higher concentration of dihydrotestosterone in carcinoma tissue the 5-alpha-reductase activity is low. Studies on the effect of androgens and antiandrogens on nuclear uptake of androgen revealed that androgens are potent stimulants of receptor translocation, while antiandrogens stimulate little or no translocation.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗