Jerry Albert

Treatment of advanced cancer of prostate with megestrol acetate

Abstract Twenty patients (16 Stage D, 4 Stage C) with prostatic cancer were treated with megestrol acetate (Megace), 160 mg. daily. Of 9 previously untreated patients, 4 had partial objective regressions (average time fourteen months to date), 4 became objectively stable (average 11.5 months), and one showed objective progression of his disease on megestrol. Among 11 patients in relapse after hormonal and/or castration therapy, one showed partial objective regression for sixteen months, 8 became objectively stable for an average of 6.8 months, and 2 showed objective progression. Bone scans either improved (40 per cent) or were stable (60 per cent) in previously untreated patients who had partial objective regression or who were objectively stable on inegestrol. Serial bone scans showed progression of disease in all previously treated patients for whom this study was available. Increased prostatic acid phosphatase decreased to normal and remained within the normal range thereafter in 4 of 6 patients in the previously untreated group; plasma testosterone fell significantly in all patients over the first two months but “escaped” toward or into the normal range in many patients after,four to six months; plasma DHeA sulfate remained significantly decreased over a twelve to eighteen-month period of observation. Since megestrol appears to be effective therapy for previously untreated prostatic cancer and since it does not cause gynecoinastia, salt retention, or thromboembolism, it should be studied further as a possible first line drug in the treatment of Stage D prostatic cancer.

Steroid levels in cancer of the prostate-markers of tumour differentiation and adequacy of anti-androgen therapy

Dihydrotestosterone (DHT) has been shown to be the major biologically active androgen in the prostate; its steady state level depends upon plasma-testosterone substrate, 5α-reductase, 3-oxidoreductase and receptor binding, all essential biochemical steps for the mediation of androgen action. In both treated and untreated patients with prostate cancer, we have studied the usefulness of tissue DHT levels as (1) biochemical markers of tumour differentiation and (2) indicators of adequacy of antiandrogen therapy. Average DHT in 29 patients with untreated cancer was 4.1 ng/g compared with an average of 5.0 ng/g in 17 patients with benign prostatic hypertrophy (P < 0.3). Non-androgen target tissues averaged 0.93 ng/g and all contained less than 1.8 ng/g. In prostate cancer tissue from 6 out of 15 patients treated with either oestrogen, castration, or both, the values were similar to the average values in untreated cancer while 9 patients had values resembling non-androgen target tissue. In previously untreated patients with Stage D carcinoma, DHT tissue concentrations were correlated with objective responses of patients to anti-androgen treatment. If tissue DHT levels greater than 2.0 ng/g are considered indicative of tumour “differentiation”, a positive correlation between “differentiated” DHT levels and response to treatment was noted in 9 of 10 previously untreated patients with prostate cancer studied to date. In the same 10 patients, histological grading correctly predicted the response to treatment in only 5 of 10 patients.

Effect of megestrol acetate on uroflow rates in patients with benign prostatic hypertrophy: Double-blind study☆

Sixty-one patients with benign prostatic hypertrophy (BPH) and decreased maximum and mean urine flow rates were randomly assigned to megestrol (Megace, 120 mg./day) or placebo therapy. The patients were studied over a five-month period with maximal and mean urine flow rates every two weeks. The patients on megestrol demonstrated significant increases in maximum and mean urine flow rates from the sixth through the twentieth weeks compared with their own control baseline values; the placebo-treated patients showed no significant changes in mean flow rates at any time point over the twenty weeks in comparison with their own baseline control values; maximum flow rates in placebo-treated patients did demonstrate statistically significant increases above their own control baseline values at eight, twelve, eighteen, and twenty weeks. Megestrol-treated patients, in comparison with the placebo group, showed statistically significant increases in maximum flow rate at fourteen, sixteen, and twenty weeks after therapy, and statistically significant increases in mean flow rate over the placebo patients at ten, twelve, fourteen, and twenty weeks. Clinical symptoms improved in 78 per cent of the megestrol-treated patients and 57 per cent of the placebo-treated patients. The side effects of megestrol were minimal except for loss of libido in 70 per cent of patients.

Prostate concentrations of endogenous androgens by radioimmunoassay.

Abstract A method for simultaneously determining concentrations of major androgens in prostate has been developed. Extraction techniques used to isolate the androgens from minced tissue include homogenization with high-speed blades in Delsals solvent mixture, adsorption to silica gel, followed by column and one thin-layer chromatography (t.l.c.). Radioimmunoassays (RIA) of small aliquots of t.l.c. eluates are used to quantitate picogram amounts of 5α-dihydrotestosterone (DHT) and 5α-androstanediols (Diol) and to estimate testosterone (T) and androstenedione (Ad). Contamination of blanks was reduced to RIA sensitivity limits primarily by treatment of glassware in a self-cleaning oven. The specificity of the method for each androgen was established by t.l.c. separations of known prostate metabolites, antisera specificities, and parallelism of sample aliquots to androgen RIA standards. The overall precision, in terms of coefficients of variation, was 21% for DHT and 24% for Diol. T and Ad could not be measured with acceptable precision because their very low concentrations in prostate (≤0.5 ng/g tissue) were less than RIA sensitivity limits. Accuracy studies indicated recoveries ranging from 96% for Diol to 121% for DHT. In human benign hypertrophie prostate tissue, DHT averaged 153 ng/g soluble protein (5.8 ng/g tissue) which was 17 times higher than values obtained in human spleen and kidney; Diol in prostate showed no consistent differences from values noted in kidney or spleen.

An improved method for extraction and determination of prostate concentrations of endogenous androgens

Abstract Our published method for determination of prostate concentrations of endogenous androgens has been modified to increase the precision, sensitivity and reliability. A more efficient tissue homogenizer (Tekmar) was used instead of the VirTis-driven blades. Silica gel adsorption of androgens in the solvent extract and subsequent separation from nonpolar lipids by selective solvent extraction in a batch process in tubes was substituted for column elution. Time, solvent and blanks were decreased. Cyproterone acetate, as a more reliable, internal relative RF marker on thin-layer chromatography (t.l.c.), replaced medrogestone. With increased sensitivity, better precision and ability to homogenize smaller tissue masses, our method was also suitable for scaling down from 1-g to biopsy-size (50 mg) specimens. The method appears to be quantitatively adequate for dihydrotestosterone (DHT), the most concentrated and biologically significant androgen in prostate, but present measurements of androstanediol ( 1 3 as concentrated as DHT in benign prostatic hypertrophy) are at least semi-quantitative.

Effect of antiandrogen and/or antiestrogen blockade on human prostate epithelial and stromal cell protein synthesis.

To evaluate the role of small amounts of DHT in prostate tissue as a stimulus to epithelial cell growth (protein synthesis) we studied tissue from patients given various androgen-blocking drugs prior to transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT in the tissue specimens. We also studied the effects on stromal cell protein synthesis of an antiestrogen, tamoxifen. Test drugs prior to TURP included Megace 160 mg per day, Megace 160 mg per day plus Tamoxifen 40 mg per day, Megace 160 mg a day plus ketoconazole 1200 mg per day and tamoxifen 40 mg/day. The tissue was processed immediately and epithelial and stromal cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labeled with either [3H]leucine or L-[35S]methionine. Stromal cells were labelled with [3H]proline. DHT was measured in whole prostate tissue. Megace alone and Megace plus tamoxifen significantly decreased both [3H]leucine incorporation into protein and tissue concentration of DHT; Megace plus ketoconazole significantly decreased L-[35S]methionine incorporation into protein and DHT. Tamoxifen significantly decreased stromal protein synthesis. When the data correlating DHT with epithelial protein synthesis using both labeling techniques were combined, the curves were parallel and a strong correlation was noted between DHT and protein synthesis over a wide range of values (P less than 0.001). These results suggest that in hormone-dependent prostate cancer even small amounts of prostate DHT such as may occur from adrenal androgens following castration may significantly stimulate growth of the tumor epithelial cells. Since tamoxifen decreased stromal protein synthesis, estrogen is likely a significant growth stimulus to the increased stromal mass characteristic of benign prostatic hypertrophy.

Tamoxifen decreases progesterone and nuclear androgen receptors in the human prostate

Androgen (AR) and progesterone (PR) receptors were measured in resected prostate tissues of patients with benign prostatic hypertrophy. One group of patients received an anti-estrogen, tamoxifen (Tm 20 mg b.i.d.) for 10 days prior to prostate resection; a second group served as controls and were untreated. Plasma levels of Tm were 200-500 pmol/ml at the time of surgery. Statistically significant decreases (P less than 0.05) were found in cytosol PR (154 fmol/mg DNA +/- 33 SE in 14 Tm-patients vs 266 +/- 40 SE in 13 untreated patients) and in nuclear AR (103 fmol/mg DNA +/- 70 SE in 18 Tm-patients vs 257 +/- 62 SE in 17 controls). Cytosol AR was not significantly different in Tm-treated patients (257 fmol/mg DNA +/- 79 SE in 15 Tm-patients vs 346 +/- 130 SE in 17 controls, P greater than 0.6). Although receptor recycling is one of several possible explanations, these decreases in progesterone and nuclear androgen receptors in Tm-treated patients suggest that estrogen has a role in the biological regulation of steroid receptors in the human prostate.

A method for tissue extraction and determination of prostate concentrations of endogenous androgens by radioimmunoassay.

A method for simultaneously determining concentrations of major androgens in prostate has been developed. Extraction techniques used to isolate the androgens from minced tissue include homogenization with high-speed blades in Delsals solvent mixture, adsorption to silica gel, followed by column and one thin-layer chromatography (TLC). Radioimmunoassays (RIA) of small aliquots of TLC eluates are used to quantitate picogram amounts of 5alpha-dihydrotestosterone (DHT) and 5alpha-androstanediols (Diol) and to estimate testosterone (T) and androstenedione (Ad). Contamination of blanks was reduced to RIA sensitivity limits primarily by treatment of glassware in a self-cleaning oven. The specificity of the method for each androgen was established by TLC separations of known prostate metabolites, antisera specificities, and parallelism of sample aliquots to androgen RIA standards. The overall precision, in terms of coefficients of variation, was 21% for DHT and 24% for Diol. T and Ad could not be measured with acceptable precision because their very low concentrations in prostate (less than or equal 0.5 ng/g tissue) were less than RIA sensitivity limits. Accuracy studies indicated recoveries ranging from 96% for Diol to 121% for DHT. In human benign hypertrophic prostate tissue, DHT averaged 153 ng/g soluble protein (5.8 ng/g tissue) which was 17 times higher than values obtained in human spleen and kidney; Diol in prostate showed no consistent differences from values noted in kidney or spleen.

The Case for Total Androgen Blockade in the Management of Metastatic Prostate Cancer

Claims have been made by Labrie et al for a dramatically improved survival and time to progression in patients with Stage D2 prostate cancer treated with total androgen blockade. (1) They used daily injections of an LHRH agonist to suppress pituitary LH and testosterone along with an antiandrogen, flutamide, to block residual prostatic DHT derived from adrenal androgens. With this therapeutic program, Labrie has claimed 90 percent survival in 52 patients followed for 2 years compared to an average survival at 2 years of 40 to 60 percent in a variety of historical controls. (1) In addition, this group has reported that progression of disease at 17 months averaged 26 percent in 88 patients, compared to 70 percent progression in a recent historical control group treated with either leuprolide (LHRH) or DES, 3 mg. per day. Recent reports of attempts to reproduce the results of Labrie et al have been unsuccessful and both Brisset et al (2) from France and Beland et al from Canada have reported no difference in time to progression or survival in relatively small numbers of patients followed for 18 months and treated with either orchiectomy alone or total androgen blockade. In view of these conflicting findings it was felt important to review the role of adrenal androgens in prostate cancer, since total androgen blockade differs from traditional therapy only in regard to the addition of adrenal blockade to blockade of gonadal androgen.