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Biomedical subjects

J Trachtenberg

Publications and source records attributed to J Trachtenberg.

At least 91 records · Page 5Linked to original sources

Hormonal management of stage D carcinoma of the prostate.

A variety of new agents is available for the hormonal treatment of prostatic cancer. None of these agents has shown itself to be superior to bilateral orchiectomy, but their individual side effects profiles may make one more appealing than another. Total androgen ablation may offer a slight survival advantage over partial androgen ablation, but this must be weighed in terms of increased side effects and overall cost. Hormonal therapy remains an effective palliative but not curative means of treating advanced prostatic cancer.

Combined Modality Therapy↗

Effectiveness of antiandrogens in the rat.

In order to determine the relative effectiveness of several antiandrogens, megace (megestrol acetate), flutamide and RU23908 were administered in optimal doses (20 mg./kg., 10 mg./kg. and 20 mg./kg.) subcutaneously daily to adult male Sprague-Dawley rats for 14 and 28 days and their effects on ventral prostate, seminal vesicles, and serum testosterone were determined. To avoid the possibility that these agents might also work through inhibition of testosterone production, all the treated animals were castrated and then implanted with a testosterone-filled silastic pellet to maintain a constant exogenous source of the androgen. A castrate placebo-treated group, an implanted placebo-treated group, and an intact placebo-treated group served as controls. The mechanisms and sites of action of the antiandrogens were thus limited to the target organs. Serum testosterone levels were equivalent at all time periods for all groups except the castrate controls which were significantly lower. The ventral prostates of the flutamide and RU23908 groups were similar and reduced 75% and 85% at 14 and 28 days respectively; the group receiving megace experienced prostatic regression of 49% and 65% which was significantly less of a reduction than that of the flutamide or RU23908 group. Results for seminal vesicle weights indicated similar trends. The administration of both steroidal (megace) and nonsteroidal (flutamide and RU23908) antiandrogens yielded a significant reduction of androgen dependent tissue weights relative to the intact control group and the implanted placebo group but still not as great a reduction as the effect produced by castration. In the rat, castration remains the optimal means of inducing regression of androgen dependent tissues.

Androgen Antagonists↗

Ketoconazole. Use in the treatment of ectopic adrenocorticotropic hormone production and Cushing's syndrome in small-cell lung cancer.

Recently, ketoconazole, an imidazole derivative with antifungal properties, has been shown to inhibit adrenal corticosteroid and androgen production. We treated a patient with small-cell lung cancer and Cushing's syndrome secondary to ectopic secretion of adrenocorticotropic hormone in whom it was necessary to discontinue chemotherapy. The patient was treated with ketoconazole, with a resultant reduction in urinary free cortisol and ketosteroid excretion and improvement in electrolyte balance. Ketoconazole may be a useful adjunct in the treatment of small-cell lung cancer or other malignancies associated with excessive corticosteroid production or as a hormonal therapy in breast or prostatic cancer.

17-Ketosteroids↗

Optimal testosterone concentration for the treatment of prostatic cancer.

In order to determine the effects of the absolute concentration of circulating androgens on normal and malignant androgen dependent tissue, normal adult male rats and rats bearing the Dunning R3327H prostatic adenocarcinoma were castrated and implanted with testosterone filled silastic pellets of 1, 3, 5, 10, 20 and 30 mm. designed to release constant amounts of testosterone, or placebo pellets. After 1 month the weights of the ventral prostate and seminal vesicles, serum testosterone and luteinizing hormone levels and the sexual activity of the normal rats were determined. The volume of the prostatic tumor was determined twice weekly for 9 weeks. Serum testosterone increased directly with the length of the implant (r = 0.986). Ventral prostate and seminal vesicle weight increased with increasing serum testosterone (r = 0.984 and r = 0.975 respectively). Changes in prostatic tumor volume did not vary with increasing serum testosterone concentration. In animals with implants of greater than 5 mm. (sig. greater than than castrate value) tumor volume increased markedly and similarly over castrate controls at 9 weeks. Animals with implants of less than or = 5 mm. had tumor volume changes identical to the castrate controls. Sexual activity was relatively normal in animals with implants of greater than 3 mm. A threshold of serum testosterone exists below which the Dunning R3327H tumor is inhibited from growing. This level is higher than the castrate level but is compatible with relatively normal sexual activity. Were there methods to determine the threshold of human tumors, therapy might be individualized to minimize side effects such as the loss of sexual activity.

Adenocarcinoma↗

Androgen receptor content of nafoxidine treated experimentally induced canine prostatic hyperplasia.

An estrogen stimulated increase in prostatic androgen receptor content has been postulated as the mechanism by which canine prostatic hyperplasia can be induced in the castrate dog treated with androstanediol and estradiol but not by androstanediol alone. In order to determine if the potent anti-estrogen Nafoxidine would inhibit this estrogen-associated development of prostatic hyperplasia, 2 week castrate young mongrel male dogs were injected for 1 month with either a) carrier solution (group 1), b) Nafoxidine (group 2), c) androstanediol and estradiol (group 3), or d) androstanediol and estradiol and Nafoxidine (group 4). At the termination of the experimental period the prostates of the animals in groups 1 and 2 were small (3.1 +/- 0.3 g (X +/- SEM) and 8.6 +/- 1.4 g respectively) and were atrophic histologically. The prostates in groups 3 and 4 were significantly heavier (24.7 +/- 3.0 g and 23.6 +/- 3.6 g respectively) than those in groups 1 and 2 and displayed glandular hyperplasia histologically. The dihydrotestosterone content of the prostatic tissue in groups 1 and 2 were similar (4.65 +/- 2.01 ng/mg DNA (X +/- SEM) and 3.13 +/- 0.65 ng/mg DNA respectively) and were significantly less than that of groups 3 and 4 (19.98 +/- 4.70 ng/mg DNA and 19.62 +/- 2.42 ng/mg DNA). The prostates of groups 3 and 4 thus displayed gravimetric, histologic and biochemical evidence of prostatic hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstane-3,17-diol↗

Ketoconazole therapy for advanced prostate cancer.

Fifteen patients with biopsy-proven prostate cancer were treated with ketoconazole 400 mg every 8 h. Two patients withdrew from therapy, one for personal reasons and one because a paraspinal mass developed. The other thirteen patients completed at least 6 months of therapy. Ketoconazole greatly reduced the need for analgesics; serum prostatic acid phosphatase levels fell to normal, and testosterone levels were reduced. After 6 months thirteen of fourteen evaluable patients were in remission. The side-effects of ketoconazole therapy were limited.

Acid Phosphatase↗

Ketoconazole therapy in advanced prostatic cancer.

To determine the effect of ketoconazole, a nonestrogenic antifungal agent, in patients with metastatic prostatic cancer 13 patients with symptomatic stage D2 prostatic cancer were administered 400 mg. ketoconazole orally every 8 hours. By 24 hours of treatment serum testosterone had decreased to the castrate level and the adrenal androgens, androstenedione and dehydroepiandrosterone, also had decreased significantly. By 1 week of treatment clinical response was evident in all patients. Pain was improved and serum prostatic acid phosphatase levels had decreased significantly, and by 1 month prostatic acid phosphatase had reached the normal range. The patients have been followed for 3 to 10 months without relapse. Side effects were few. Because of the ease of administration, rapidity of action, and decrease of adrenal and testicular androgen levels, as well as the relative lack of side effects, ketoconazole may prove to be an important new drug in the treatment of prostatic cancer.

Acid Phosphatase↗

The effects of ketoconazole on testosterone production and normal and malignant androgen dependent tissues of the adult rat.

Ketoconazole is a potent inhibitor of the P450 series of enzymes that are essential for the production of androgens. In order to determine the effects of ketoconazole on androgen production and androgen dependent tissues in the rat, adult male rats were administered varying doses of ketoconazole every 12 hours. Serum testosterone declined to unmeasurable levels at ketoconazole doses of greater than 4 mg. This dose was sufficient to completely inhibit the testosterone surge induced by the administration of a potent luteinizing releasing hormone agonist. The ventral prostate weight of normal rats and the volume of the Dunning R3327H androgen dependent prostatic cancer declined at the same rate in animals treated with ketoconazole or castration. Ketoconazole may be an effective agent to treat androgen dependent diseases.

Adenocarcinoma↗

A comparison of a powerful luteinizing hormone releasing hormone analogue agonist and estrogen in the treatment of advanced prostatic cancer.

Luteinizing hormone releasing hormone agonists presently are being evaluated in the treatment of patients with metastatic prostatic cancer. To determine the comparative benefits of a specific luteinizing hormone releasing hormone agonist [6-leu (1-9) luteinizing hormone releasing hormone nonapeptide ethylamide] relative to conventional estrogen therapy 23 patients with stage D2 prostatic cancer were randomized to receive either 1 mg. luteinizing hormone releasing hormone agonist daily (12) or 3 mg. diethylstilbestrol per day (11). Both agents were effective in inducing a remission in all patients, although diethylstilbestrol was slightly faster. The early phase of treatment with the luteinizing hormone releasing hormone agonist was dominated by a transient reversible deterioration (the flare) of the patient, which was believed to be related to the agonist-induced increase in serum androgens. At 1 year of followup adverse effects in both groups have been minor but the proportion of patients with progression in the luteinizing hormone releasing hormone agonist group (6 of 12) was significantly higher than that in the diethylstilbestrol group (0 of 11). Further investigation is required to determine the role of luteinizing hormone releasing hormone agonist in the treatment of patients with advanced prostatic cancer.

Aged↗

Ketoconazole: a novel and rapid treatment for advanced prostatic cancer.

Ketoconazole is an orally administered broad-spectrum antifungal agent that acts through the inhibition of the steroid synthetic pathways. At high doses in humans ketoconazole can lower rapidly serum testosterone and maintain it in the castrate range with frequent administration. This property suggested that ketoconazole might be useful in the treatment of prostatic cancer. We report a case of prostatic cancer in which ketoconazole resulted in rapid and sustained reduction in serum androgens as well as rapid induction of a clinical remission. Ketoconazole may be a valuable agent in the treatment of prostatic cancer.

Aged↗

The treatment of metastatic prostatic cancer with a potent luteinizing hormone releasing hormone analogue.

Metastatic prostatic cancer generally is treated by either castration or the administration of exogenous estrogens, both of which have significant clinical disadvantages. Luteinizing hormone releasing hormone analogues have been shown to suppress gonadal steroidogenesis in animals and humans. To assess the effect of the administration of a potent luteinizing hormone releasing hormone analogue, (D-Leu-6)luteinizing hormone releasing hormone (1-9) nonapeptide ethylamide, 9 patients with previously untreated stage D2 prostatic cancer were treated with this agent for 3 to 8 months. By 3 months of treatment all patients demonstrated a significant decrease in serum testosterone and a decreased peak serum luteinizing hormone and testosterone response to the acute administration of the analogue, with no change in baseline serum luteinizing hormone or prolactin. These data suggest that this analogue acts by decreasing the pituitary release of luteinizing hormone. No major adverse effects were noted with this treatment modality, and all patients were symptomatically improved and demonstrated a decrease or stabilization in tumor activity as measured by prostatic computerized tomography or ultrasound scan, prostatic acid phosphatase and bone scan. A representative case is presented. Luteinizing hormone releasing hormone analogues may prove to be valuable new agents in the treatment of advanced prostatic cancer.

Aged↗

The effect of the chronic administration of a potent luteinizing hormone releasing hormone analog on the rat prostate.

In order to assess the effect of the chronic administration of a potent luteinizing hormone releasing hormone analog, (D-SER(But)6) LHRH (1-9) nonapeptide-ethylamide (Buserelin, HOE 766) on the pituitary gonadal axis, and the prostate, adult male Wistar rats were administered either 0, 3, 10 or 50 micrograms./kg. body weight Buserelin subcutaneously daily. At 7, 21, 35 and 42 days of treatment, groups of animals were sacrificed and certain serum endocrine and grave metric parameters determined. In addition, at 1, 21 and 42 days of treatment the 1-hour response of serum LH and serum testosterone to a single injection of 10 micrograms./kg. body weight Buserelin was determined. All treatment doses had similar effects. Serum prolactin and the basal and "acute" response of serum LH to Buserelin (+ delta 5,000 per cent) were unaltered throughout treatment. Testes weight, testicular LH receptor content, and basal and "acute" concentrations of serum testosterone were markedly decreased by 42 days of treatment (48, 89, 88 and 88 per cent, respectively). Although seminal vesicle weight declined 50 per cent at 42 days of treatment, prostate weight was not altered from initial weight, but was significantly lower than age matched control at 42 days of treatment. Buserelin remains a potent stimulator of pituitary LH release even during chronic administration. It markedly reduces serum testosterone through a predominant testicular site of action. Buserelin treatment inhibits the growth of the normal prostate, but does not cause its regression.

Animals↗

Correlation of prostatic nuclear androgen receptor content with duration of response and survival following hormonal therapy in advanced prostatic cancer.

To assess whether pre-treatment prostatic androgen receptor measurements would be of value in predicting the response to hormonal therapy in patients with prostatic cancer 23 men with metastatic carcinoma of the prostate underwent prostatic biopsy before treatment. Cytosolic and nuclear prostatic androgen receptor contents were measured by a single saturating dose, dextran-charcoal assay. All patients had measurable levels of androgen receptor in prostatic tissue and all demonstrated objective evidence of improvement following hormonal therapy. Thus, if androgen receptor measurements are to be useful in predicting prognosis correlations between quantitative levels of receptor and quantitative aspects of response must be established. In our study response was quantitated by measuring the duration of response and survival following hormonal treatment. The strong correlation between duration of response and survival (p less than 0.01) demonstrated herein suggests that survival in these patients is related directly to the duration of time patients respond to hormonal therapy. Neither total cellular nor cytosolic androgen receptor content correlated with response. However, nuclear androgen receptor content correlated with the duration of response and survival following hormonal treatment (p less than 0.05). Furthermore, in patients with nuclear receptor levels less than 110 fmol. per mg. deoxyribonucleic acid the duration of response (7.1 plus or minus 3.8 months) and survival (14.4 plus or minus 5.9 months) was significantly shorter than in patients with higher levels of nuclear receptor (17.3 plus or minus 10.4 and 24.7 plus or minus 8.8 months, respectively) (p less than 0.05). These findings, which are the first report of a correlation between nuclear androgen receptor content and hormonal responsiveness, suggest that measurements of nuclear receptor may aid in identifying those patients unlikely to obtain a prolonged response from hormonal therapy.

Acid Phosphatase↗

Androgen receptor content of normal and hyperplastic human prostate.

In an effort to determine whether human benign prostatic hyperplasia (BPH) is characterized by an increase in androgen receptor content, the levels of nuclear and cytosolic androgen receptors were quantitated in normal prostatic tissue obtained from five young men (mean age /+- SEM, 26 +/- 3 yr) and in hyperplastic (periurethral) and peripheral prostatic tissues obtained from nine older men (mean age, 62 +/- 2 yr). There was no significant difference between the cytosolic or nuclear androgen receptor content of the hyperplastic, peripheral, or normal prostatic tissue. Thus, in this study we were unable to identify an increase in androgen receptor content in BPH. These findings fail to support the hypothesis that increases in androgen receptor content are involved in the pathogenesis of human BPH.

Adult↗

Methods for the determination of androgen receptor content in human prostatic tissue.

Human prostatic androgen receptor content can be measured reliably in either fresh or bulk tissue stored in liquid nitrogen using (3H) R 1881 at incubation conditions of 4 C for 20 hr. Powdered tissue stored in liquid nitrogen for more than 12 days shows a marked deterioration in receptor content. Although multiple point dextran coated charcoal assays analyzed by Scatchard plot are preferable for receptor quantitation of bulk tissue, the single saturating dose assay provides useful information on needle biopsy specimens. When this technique is used to evaluate samples with protein concentrations less than 1 mg per ml, the use of hydroxylapatite to separate receptor bound and free steroid is superior to the use of dextran coated charcoal. The addition of sodium molybdate to the homogenization buffers results in a marked increase in cystosolic androgen receptor content and a decrease in extractable nuclear receptor content. The use of a vertical rotor to ensure short centrifugation times enhances the reliability of sucrose density gradient analyses of human prostatic androgen receptor.

Adsorption↗

Androgen- and estrogen-receptor content in spontaneous and experimentally induced canine prostatic hyperplasia.

To gain insight into the mechanism by which steroidal hormones influence the development of canine prostatic hyperplasia, nuclear and cytosolic androgen- and estrogen-receptor content, as measured under exchange conditions by the binding of [(3)H]R1881 (methyltrienolone) and [(3)H]estradiol, respectively, were quantitated in the prostates of purebred beagles of known age. In young dogs with spontaneously arising and experimentally induced (androstanediol plus estradiol treatment) prostatic hyperplasia, nuclear, but not cytosolic, prostatic androgen-receptor content was significantly greater than that determined in the normal prostates of age-matched dogs (3,452+/-222 and 4,035+/-274 fmol/mg DNA vs. 2,096+/-364 fmol/mg DNA, respectively). No differences were observed between the androgen-receptor content of the normal prostates of young dogs and the hyperplastic prostates of old dogs. The cytosolic and nuclear estrogen-receptor content of spontaneously arising prostatic hyperplasia in both young and old animals was similar to that found in normal prostates. The administration of estradiol plus androstanediol to castrate dogs significantly increased the prostatic nuclear androgen-receptor content over that found in dogs treated only with androstanediol. This estradiol-associated increase in nuclear androgen-receptor content was accompanied by the development of benign prostatic hyperplasia. Estradiol treatment of castrate dogs resulted in an increase in prostatic nuclear estrogen-receptor content, in the appearance of a putative prostatic cytosolic progesterone receptor, and in an alteration of the epithelium of the prostate to one characterized by squamous metaplasia. Treatment of castrate dogs with both estradiol and androstanediol resulted in a reduction in prostatic nuclear estrogen-receptor content, disappearance of the progesterone receptor, and loss of squamous metaplasia. An increase in nuclear androgen-receptor content, thus, appears to be an important event in the development of both spontaneously arising and experimentally induced canine prostatic hyperplasia. The mechanism of androgen-estrogen synergism in the experimental induction of canine benign prostatic hyperplasia may be explained by estradiol-mediated increases in nuclear androgen-receptor content. Because androstanediol blocked certain estradiol-mediated events within the prostate, a negative feedback mechanism may exist in which the response of the canine prostate to estrogens is modulated by rising levels of androgen.

Androstane-3,17-diol↗