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J Geller

Publications and source records attributed to J Geller.

At least 91 records · Page 5Linked to original sources
PubMed1988

Advantages of total androgen blockade in the treatment of advanced prostate cancer.

Total androgen blockade has been proposed as a better therapeutic technique than castration alone for the management of metastatic prostate cancer. This is based on the theory that links adrenal androgens to tumor growth. We have carefully examined the role of adrenal androgens in prostate cancer. Work done in our laboratory, as well as the work of many others, has demonstrated the following in regard to the role of adrenal androgens in prostate cancer: (1) The adrenal cortex secretes significant amounts of adrenal androgens into the blood. (2) Adrenal androgens are converted into dihydrotestosterone (DHT), as indicated by studies of labeled DHT recovered from prostates resected one-half hour after infusion of 3H-androstenedione or 3H-dehydroepiandrosterone sulfate into patients. We have also shown that biopsies of prostates from patients who were previously castrated may contain significant amounts of DHT, which could only be derived from adrenal androgens. (3) We have quantified DHT derived from adrenal androgens by measuring prostate DHT concentrations in castrates and in patients treated with combined gonadal and adrenal blockade. The mean difference between these two groups, 0.32 ng/g of DHT lower with combined blockade, is statistically significant and represents DHT derived from adrenal androgens. (4) We have also demonstrated that the small amounts of DHT derived from adrenal androgens may be biologically significant in stimulating prostatic epithelial cell protein synthesis in humans; others have reported similar findings in animals. (5) A review of patients in relapse after castration, who are treated with adrenal androgen blockade, indicates that approximately one out of three patients will show an objective remission based on National Prostate Cancer Project (NPCP) criteria. Despite data supporting the importance of adrenal androgens in prostate cancer, clinical trials using combined adrenal and gonadal blockade in prostate cancer have shown only modest benefit over castration. The largest and best study to date is the Southwest Oncology Group (SWOG) study, which did show a near-significant (P less than 0.065) difference between patients treated for 20 months with a luteinizing hormone-releasing hormone (LH-RH) plus flutamide compared with LH-RH alone. The difference in median time to progression was approximately 2 months between the groups. However, when one considers the fact that two out of three patients are probably not responding to the total androgen blockade, the 2 month difference may actually represent 6 or more months in a subset of one-third of patients receiving that therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex↗
PubMed1987

Effects of castration compared with total androgen blockade on tissue dihydrotestosterone (DHT) concentration in benign prostatic hyperplasia (BPH).

We compared the effect of a variety of drug regimens to lower prostate DHT concentration. Patients with BPH were treated for one week prior to surgery with either tamoxifen, flutamide, megestrol acetate, megestrol acetate plus tamoxifen and megestrol acetate plus DES or ketoconazole. DHT concentration in the surgically resected tissue was compared with tissues obtained from untreated patients. We also obtained prostate tissue at the time of relapse in patients with prostate cancer who had been treated with orchiectomy with or without estrogen therapy. Megestrol acetate plus the mini-dose of DES (0.1 mg) and megestrol acetate plus ketoconazole both decreased DHT concentrations in prostate tissue to levels (0.79 ng/g) significantly below those noted with orchiectomy (1.16 ng/g). The difference between the DHT concentration in the two groups (orchiectomy vs. total androgen blockade) represents the contribution of adrenal androgens to prostate tissue DHT. This small amount of DHT (approximately 0.4 ng/g) may be biologically important in stimulating prostate epithelial cell growth.

Androgen Antagonists↗
PubMed1987

Relationship between human prostatic epithelial cell protein synthesis and tissue dihydrotestosterone level.

To evaluate the role of small amounts of prostatic tissue dihydrotestosterone (DHT) as a stimulus to epithelial cell protein synthesis, we studied tissue from 27 patients given various androgen-blocking drugs for 1 week before transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT levels in the tissue specimens. Test drugs before TURP included megestrol acetate 160 mg per day, with and without Tamoxifen 40 mg per day, or ketoconazole 1200 mg per day. The tissue was processed immediately and epithelial cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labelled with either 3H-leucine or L-35S-methionine. The DHT level was measured in whole prostatic tissue. Megestrol acetate alone and with tamoxifen significantly decreased both the incorporation of 3H-leucine into protein and the tissue concentration of DHT; megestrol acetate plus ketoconazole significantly decreased L-35S-methionine incorporation into protein and the DHT level. When the data correlating DHT with protein synthesis using both labelling 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 prostatic cancer even small amounts of prostatic DHT such as may occur from adrenal androgens following castration may significantly stimulate protein synthesis of the tumour epithelial cells.

Aged↗
PubMed1986

Tropoelastin production and tropoelastin messenger RNA activity. Relationship to copper and elastin cross-linking in chick aorta.

The elastin content of the chick thoracic aorta increases 2--3-fold during the first 3 weeks post-hatching. The deposition of elastin requires the covalent cross-linking of tropoelastin by means of lysine-derived cross-links. This process is sensitive to dietary copper intake, since copper serves as cofactor for lysyl oxidase, the enzyme that catalyses the oxidative deamination of the lysine residues involved in cross-link formation. Disruption of cross-linking alters tissue concentrations of both elastin and tropoelastin and results in a net decrease in aortic elastin content. Autoregulation of tropoelastin synthesis by changes in the pool sizes of elastin or tropoelastin has been suggested as a possible mechanism for the diminished aortic elastin content. Consequently, dietary copper deficiency was induced to study the effect of impaired elastin cross-link formation on tropoelastin synthesis. Elastin in aortae from copper-deficient chicks was only two-thirds to one-half the amount measured in copper-supplemented chicks, whereas copper-deficient concentrations of tropoelastin in aorta were at least 5-fold higher than normal. In spite of these changes, however, increased amounts of tropoelastin, copper deficiency and decreased amounts of elastin did not influence the amounts of functional elastin mRNA in aorta. Likewise, the production of tropoelastin in aorta explants was the same whether the explants were taken from copper-sufficient or -deficient birds. The lower accumulation of elastin in aorta from copper-deficient chicks appeared to be due to extracellular proteolysis, rather than to a decrease in the rate of synthesis. Electrophoresis of aorta extracts, followed by immunological detection of tropoelastin-derived products, indicated degradation products in aortae from copper-deficient birds. In extracts of aortae from copper-sufficient chicks, tropoelastin was not degraded and appeared to be incorporated into elastin without further proteolytic processing.

Animals↗
PubMed1986

Effects of androgen blockade with ketoconazole and megestrol acetate on human prostatic protein patterns.

We studied the effects of megestrol acetate (MA) and ketoconazole (KC) on protein synthesis of epithelial and stromal cells of human prostate. Patients with benign prostatic hypertrophy (BPH) were treated with MA (160 mg/day) plus KC (1,200 mg/day) for 7 days. Prostate tissues obtained from transurethral resection (TURP) were separated into epithelial and stromal cells with 0.5% collagenase. The separated cells were incubated with L-35S-methionine in methionine-free MEM at 37 degrees C for 3 hr. The protein synthesis in both epithelial and stromal cells was significantly inhibited in the group treated with MA and KC when compared to a control group (p less than 0.05). The proteins incorporated with L-35S-methionine were analyzed by SDS-PAGE and autoradiography. The molecular weights of the epithelial and stromal proteins inhibited ranged between 35-55K.

Androgen Antagonists↗
PubMed1986

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.

Dihydrotestosterone↗
PubMed1985

DHT in prostate cancer tissue--a guide to management and therapy.

In 24 untreated stage D2 prostate cancer patients with prostate DHT levels greater than 2.5 ng/g, 20 initially responded to therapy with partial objective progression (POR) or were objectively stable (OS) for 12 or more months while four patients relapsed in less than 1 year. Of eight patients with prostate DHT levels less than 2.0 ng/g, five had either objective progression or were objectively stable for 6 months or less; two other patients have completed remissions ranging from 16 to 24 months while one patient remains objectively stable for 21 months to date. DHT concentrations were also measured in prostate tissue of patients with advanced prostate cancer in relapse following either DES or castration with or without estrogen therapy. Although castration, medical or surgical, usually leads to DHT concentrations of less than 2.4 ng/g, two out of 20 surgical castrates and four out of nine estrogen-treated patients had values above this level. These differences suggest that (1) increased tissue DHT levels of DES-treated patients may be due to inadequate dosage or decreased compliance, and (2) increased tissue DHT concentrations greater than 2.4 ng/g in castrates suggests an adrenal cortical androgen contribution to the prostate DHT level. These studies suggest that DHT measurements in prostate cancer tissue are of value in predicting response in untreated prostate cancer patients and of directing therapy in patients who are in relapse after orchiectomy or estrogen therapy.

Castration↗
PubMed1985

Adrenal androgen blockade in relapsed prostate cancer.

The effectiveness of aminoglutethimide as an adrenal inhibitor has been well-documented by decreases in plasma testosterone and delta 4 levels, which fall significantly following the drug in previously orchiectomized patients. The use of cortisone or cortisol along with aminoglutethimide complicates the interpretation of the role of aminoglutethimide in effecting clinical responses. However, since physiologic replacement doses were used in most cases, a significant role for cortisone in effecting a clinical response is unlikely. Aminoglutethimide does have side-effects including rash and lethargy. It requires administration of replacement doses of cortisone and sometimes mineralocorticoid as well since it inhibits adrenal steroid synthesis in all pathways. Peripheral adrenal androgen inhibitors, such as flutamide, Megace, cyproterone acetate or 5 alpha-reductase inhibitors, in the future may be equally effective and simpler to administer than aminoglutethimide but objective and adequate numbers of studies using acceptable objective criteria must be done in order to adequately compare these drugs to aminoglutethimide. There appears to be approximately a 33% response rate (partial objective regression and objectively stable) following blockade of adrenal androgens in patients in relapse after castration. Blockade of adrenal androgen is certainly more tolerable and has many fewer side-effects than the alternative of chemotherapy which does not give response rates in most cases that are significantly different from those noted with aminoglutethimide. Murray's paper, combined with prior studies by Drago et al., goes a long way in establishing adrenal androgen blockade with that drug as the next step to be taken in patients following relapse from prior castration (medical or surgical). The most important question revolves around the timing of adrenal androgen blockade. As stated by Murray, will adrenal androgen blockade provide better survival if given earlier following relapse? The answer is not known yet. The answer may come from the work of Labrie [1], Geller and Albert [2] and others, who suggest that total survival in prostate cancer may be improved with blockade of adrenal androgens not after relapse following castration, but with panandrogen blockade at the time of initial therapy for prostate cancer.

Adrenalectomy↗
PubMed1985

Acute effects of testicular and adrenal cortical blockade on protein synthesis and dihydrotestosterone content of human prostate tissue.

To examine the relationship between whole prostatic dihydrotestosterone (DHT) concentrations and epithelial and stromal protein synthesis, patients awaiting surgery for benign prostatic hypertrophy were given medication to reduce circulating and tissue androgen levels for comparison to levels in untreated patients. The medications, either megestrol acetate, a progestational antiandrogen, or megestrol acetate plus dexamethasone, were given for 1 week before surgery. Aliquots of prostate tissue obtained at surgery were assayed for DHT. The remainder of the tissue was separated into stromal and epithelial cells using enzymatic separation; the incorporation of both [3H] proline into stromal protein and [3H]leucine into epithelial cell protein was then measured. Over a wide range of tissue DHT concentrations, DHT correlated significantly with [3H]proline incorporation into stromal protein (r = 0.58). Likewise, epithelial cell incorporation of [3H]leucine into protein correlated significantly with tissue DHT concentrations, with a r value of 0.79. In the case of stromal cells, no additional effects of dexamethasone given with megestrol acetate were found on stromal protein synthesis. Epithelial cell [3H]leucine incorporation into protein was paradoxically enhanced by dexamethasone plus megestrol acetate compared to the latter alone, despite the fact that tissue DHT and circulating adrenal androgens, dehydroepiandrosterone sulfate and delta 4-androstenedione, were not significantly different from values obtained after treatment with megestrol acetate alone. These studies support the conclusion that there is a dominant role of DHT in regulating protein synthesis in both prostatic epithelial and stromal cells. Dexamethasone appears to have a growth-stimulating effect on prostatic epithelial cells.

Adrenal Cortex↗
PubMed1985

Rationale for blockade of adrenal as well as testicular androgens in the treatment of advanced prostate cancer.

Hormonal therapy for metastatic prostate cancer blocks the androgen-mediated action that stimulates the hormone-dependent clone of tumor cells. Such therapy must be directed at all sources of tissue dihydrotestosterone (DHT), including testosterone derived from the testis. Adrenal androgens such as dehydroepiandrosterone (DHEA) sulfate, DHEA, and androstenedione may also diffuse into prostate cells, and although their conversion to DHT is in the range of only 3% to 7% (compared to 50% to 70% for testosterone), the large amount (four to six times that of testosterone) of adrenal androgen substrate may account for up to one sixth of total prostate DHT. The role of adrenal androgens as potential stimuli to the hormone-dependent clone of tumor cells is further supported by studies in which significant amounts of DHT were found in the prostates of patients in clinical relapse after surgical castration. There are reports indicating that both surgical and medical adrenalectomy produce subsequent remissions in about 30% of patients who failed after castration or estrogen. The rationale to suppress all sources of DHT, therefore, is clear. To accomplish this goal successfully, megestrol acetate was combined with DES or estradiol to suppress testicular function to castration levels and to block residual adrenal androgens at the cell level. Studies are underway to compare clinical disease-free intervals in these patients to those patients receiving traditional therapy of castration and estrogen.

Adrenal Glands↗
PubMed1984

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.

Cell Nucleus↗
PubMed1984

Comparison of prostatic cancer tissue dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy.

Dihydrotestosterone concentrations have been measured in prostatic tissue from patients with recurrent advanced prostatic cancer after 1.0 to 5.0 mg. diethylstilbestrol per day or castration with or without estrogen therapy. Although medical or surgical castration usually leads to tissue dihydrotestosterone concentrations of less than 2.4 ng./gm. 2 of 20 surgically castrated and 4 of 9 estrogen-treated patients had values above this level. The difference between the number of patients with dihydrotestosterone levels greater than 2.4 ng./gm. in the surgical castrated and estrogen-treated groups was statistically significant by a chi-square test. These differences suggest that 1) increased tissue dihydrotestosterone levels in diethylstilbestrol-treated patients may be caused by inadequate dosage or decreased compliance, and 2) increased tissue dihydrotestosterone concentrations greater than 2.4 ng./gm. in castrated patients suggest an adrenocortical androgen contribution to the prostatic dihydrotestosterone level. Therefore, patients who are castrated or treated with diethylstilbestrol should have plasma testosterone and tissue dihydrotestosterone measurements at the time of relapse. If plasma and tissue dihydrotestosterone levels are at castrate levels (plasma levels less than 0.5 ng./ml. and tissue levels less than 2.4 ng./gm.) then further hormonal therapy is not indicated. Otherwise, adrenocortical suppression should be done if plasma testosterone is at castrate levels and tissue dihydrotestosterone is elevated. When plasma testosterone is above castrate levels titration with hormonal therapy should be done while plasma testosterone is monitored to achieve plasma testosterone levels below 0.5 ng./ml.

Castration↗
PubMed1984

Arson: an unforeseen sequela of deinstitutionalization.

Did the shift from institutional to community-based services brought about by deinstitutionalization affect the nature or function of pathological fire setting? The author studied admissions to a state hospital that were precipitated by arson. During a 200-day period, 14 patients accounted for 16 admissions and 17 fires. The data indicate that fires are set by consumers of public sector mental health services to communicate a wish or a need for a change in location of those services. Communicative arson has caused property damage, personal injury, and death and has resulted in a backlash against community alternatives for psychiatric treatment.

Adolescent↗
PubMed1984

Tissue dihydrotestosterone levels and clinical response to hormonal therapy in patients with advanced prostate cancer.

Dihydrotestosterone (DHT) levels were measured by RIA in tumor tissue from 32 men with advanced prostate cancer and correlated with their clinical responses to antiandrogen therapy. In 24 patients with tumor tissue DHT levels greater than 2.5 ng/g, 20 initially responded to therapy with partial objective regression or were objectively stable for 12 or more months, while 4 patients relapsed in less than 1 yr. The average disease-free interval in this group was 24 months, with 9 patients still continuing in partial objective regression or objective stability. Of 8 patients with DHT levels less than 2.0 ng/g, 5 had either objective progression or were objectively stable for 6 months or less; 2 other patients have completed remissions ranging from 16-24 months, while 1 patient remains objectively stable for 21 months to date. The average disease-free interval in patients with DHT levels less than 2.0 ng/g was 9.75 months, which is significantly less (P less than 0.001) than that of patients with DHT levels greater than 2.5 ng/g. There was no discernible relationship between the Gleason histological grade of prostate cancer and initial clinical response to therapy in these same patients. In summary, this study supports the thesis that tissue DHT levels may be a useful marker for predicting the clinical response of prostate cancer to antiandrogen therapy.

Androgen Antagonists↗
PubMed1984

Effect of tamoxifen on stromal protein synthesis in the human prostate.

To test the hypothesis that estrogen may have significant biological effects on the human prostate, we studied the effects of in vivo administration of tamoxifen, an antiestrogen, on human prostatic stromal protein synthesis in vitro. This was done by measuring [3H]proline incorporation in vitro in stromal cells separated enzymatically with 0.5% collagenase and trypsin from hypertrophic prostatic tissue removed at surgery. A mechanical method for separation of epithelium and stroma was attempted, but cell damage resulted in very low incorporation of [3H]proline into protein. Twelve patients were given 20 mg tamoxifen twice daily for 10 days before surgery. The serum levels of tamoxifen at the time of surgery ranged from 200-500 pmol/ml. Control tissues (14) were obtained from untreated patients. Tamoxifen decreased stromal protein synthesis, as measured by counts per min/mg protein, to approximately one third of that found in control patients (control mean, 102,428; tamoxifen-treated mean, 34,111; P less than 0.01). These results support the concept that estrogen has a significant role in the regulation of stromal protein synthesis and the pathophysiology of benign prostatic hypertrophy.

Cell Separation↗
PubMed1983

Comparison of various hormonal therapies for prostatic carcinoma.

The goals of hormonal therapy for prostatic cancer are to decrease circulating plasma testosterone to castration levels; prevent a rise in or reduce circulating prolactin; and block residual androgen at the cell level. Orchiectomy is very effective but does not prevent residual adrenal androgens from being converted to dihydrotestosterone (DHT); also, it has no effect on plasma prolactin. Estrogen has no known effect on androgen-receptor concentration or DHT binding to receptor and raises plasma prolactin. It also has significant side effects. Megestrol acetate, the only antiandrogen currently available for use in the United States, has been shown to block androgen from all sources. It produces a transient reduction in plasma testosterone to levels somewhat higher than those in castrated men, and it has no effect on plasma prolactin. When used in a dose of 120 mg/day in combination with 0.5 to 1.5 mg of estradiol per day, it acts synergistically to suppress pituitary gonadotropins and maintain plasma testosterone at castration levels for periods of up to 1 year. Newer therapies being studied include flutamide, a nonsteroidal antiandrogen, and luteinizing hormone-releasing hormone (LHRH). Data on these agents are limited and comparisons with standard therapies are needed.

Androgen Antagonists↗