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PubMed1994

Inhibitory effects of analogs of luteinizing hormone-releasing hormone on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer.

The effects of treatment with the luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and agonist [D-Trp6] LH-RH were investigated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R-3327-AT-1 prostatic adenocarcinoma implanted orthotopically into the ventral lobes of prostate glands. The LH-RH antagonist SB-75 and the LH-RH agonist [D-Trp6] LH-RH were administered from osmotic minipumps and the survival time of animals bearing this cancer was evaluated. Treatment with SB-75 and [D-Trp6] LH-RH significantly prolonged the mean survival time of rats by 4.1 days and 4.5 days, respectively. In cell cultures, proliferation of the AT-1 cell line was strongly inhibited by the antagonist SB-75, but only a moderate suppression of tumor cell growth in vitro was observed with the agonist [D-Trp6] LH-RH. Receptor assays on Dunning R-3327-AT-1 tumor membranes showed high-affinity binding sites for LH-RH, epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). Receptors for EGF were significantly down-regulated by treatment with SB-75. Therapy with SB-75 also decreased EGF levels in tumor tissue to non-detectable levels, as measured by specific RIA. Our results demonstrate that the LH-RH antagonist SB-75 and agonist [D-Trp6] LH-RH inhibit the growth of androgen-independent Dunning R-3327-AT-1 prostatic cancer in vivo and in vitro.

Androgens↗

PubMed1980

LH-RH agonists and antagonists.

Large doses of stimulatory analogues of luteinizing hormone-releasing hormone (LH-RH) caused paradoxical antifertility effects. These effects are being utilized for the possible development of contraceptive methods. Several inhibitory analogues of LH-RH have been tested in men and women and shown to be active. The synthetic approach based on inhibitory analogues of LH-RH has been proven to be feasible for development of new methods of birth control. Continued research and testing along these lines may lead to the development of contraceptives based on inhibitory analogues of LH-RH that could be conveniently applied as a nasal spray and could be free of undesirable side effects.

Animals↗

PubMedDate not supplied

Combined treatment with an LHRH agonist and testosterone in man. Reversible oligozoospermia without impotence.

We have previously shown that LHRH agonist [D-Trp6,Pro9-NEt]LHRH (LHRHA) results in reversible oligozoospermia when given to normal subjects for up to ten weeks. A fall in plasma testosterone was accompanied by loss of libido and potency. We now report six subjects who were evaluated by semen analysis and hormone profile at two-week intervals during ten-week basal, 20-week treatment, and post-treatment periods lasting at least ten weeks. Treatment consisted of LHRHA (50 microgram subcutaneously daily), and testosterone enanthate (100 mg intramuscularly every two weeks). Sperm density (mean basal 76.7 +/- 8.7 x 10(6)/ml) fell consistently in each subject to a mean nadir of 12.3 +/- 4.5 x 10(6)/ml (p less than 0.001). This is similar to the mean nadir of 11.6 +/- 5.8 x 10(6)/ml achieved when LHRHA was given alone. In each individual subject, sperm density returned to his basal level after cessation of treatment. No consistent changes were seen in sperm motility of morphology, or in semen volume. Libido and potency were maintained in all subjects. An additional three subjects received testosterone enanthate alone in identical dosage for 20 weeks. No change in sperm density was observed. In contrast to treatment with LHRHA alone, combination treatment produces reversible oligozoospermia without attendant change in potency.

Adult↗

PubMedDate not supplied

Heterogeneity of sperm density profiles following 20-week therapy with high-dose LHRH analog plus testosterone.

Eight normal male volunteers received an LHRH analog, 100 to 500 micrograms daily, for 20 weeks. Testosterone enanthate, 100 mg, was given by injection every second week. Sperm density fell to 5.5 X 10(6)/ml and to 0 in two of the subjects receiving 100 micrograms, but was unchanged in the third. Three of the subjects who received 500 micrograms displayed azoospermia, whereas the other two showed no significant change in sperm density. The reasons for the heterogeneity are not clear. Only one of the three nonresponders had testosterone values that were higher than the other subjects. Gonadotropin levels were similar in responders and nonresponders. It is possible that the response to LHRH analog in man is determined by the extent of the reduction in LH bioactivity.

Adult↗

PubMedDate not supplied

Prolonged suppression of plasma LH levels in male rats after a single injection of an LH-RH agonist in poly(DL-lactide-co-glycolide) microcapsules.

The authors have examined the effects of a subcutaneous injection of the LH-RH agonist D-Trp6-LH-RH formulated in biodegradable poly(DL-lactide-co-glycolide) microcapsules on plasma levels of D-Trp6LH-RH, LH, and PRL in adult, gonadectomized male rats. Immunoreactive D-Trp6-LH-RH was detectable in the plasma of these animals at 1, 2, 3, and 4 weeks after injection. LH concentrations were greatly reduced 1 week after administering the D-Trp6-LH-RH microcapsule, continued to decrease during the following week, and remained suppressed until the end of the study, 6 weeks after the injection. Plasma PRL levels appeared elevated 1 to 2 weeks after the injection and suppressed thereafter, but these effects were significant only in animals rendered hyperprolactinemic by transplantation of an isologous pituitary under the renal capsule. These results demonstrate that an LH-RH agonist formulated in biodegradable microcapsules and administered as a subcutaneous injection can exert marked biologic effects in rats for at least 6 weeks. These findings also suggest that prolonged exposure to an LH-RH agonist may first produce stimulation, followed by an inhibition of PRL release from both in situ and ectopic pituitaries.

Animals↗

PubMedDate not supplied

Normal gonadal functions and fertility after 23 months of treatment of prepubertal male and female dogs with the GnRh agonist [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide.

The GnRH agonist [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide was administered to prepubertal male and female dogs daily for 23 months by subcutaneous injection. During GnRH agonist treatment, plasma steroid levels, namely dehydroepiandrosterone, androst-5-ene-3 beta-17 beta-diol, androstenedione, testosterone, dihydrotestosterone, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane, 3 beta, 17 beta-diol were markedly inhibited in male animals, whereas in female animals, the plasma concentration of DHEA and delta 5-diol were decreased. Within 2 months following cessation of therapy, all steroids increased to normal adult levels. Morphological studies reveal that treatment of male animals with the GnRH agonist is accompanied by a small volume of seminiferous tubules, Leydig cells, and prostate gland, whereas in the ovaries of female animals, there is a large number of primordial follicles, a few primary follicles, but no secondary follicles. In the pituitary gland of animals of both sexes, LH-secreting cells have high levels of glycogen particles in their cytoplasm and tend to be either of normal appearance with dilated rough endoplasmic reticulum (RER) or strongly atrophied with a dark-stained cytoplasm, a contraction of RER, and a decrease in the number of secretory granules. Reticular cells of the connective tissue also show high levels of glycogen particles. After the 14 month recovery period, spermatogenesis has a normal adult appearance, the prostate gland shows a normal secretory epithelium, and secondary follicles are easily observed in the ovary. Gonadotrophs are free of glycogen accumulation, but reticular cells continue to show an accumulation of glycogen particles in their cytoplasm. Two male and two female animals were mated after the recovery period and produced normal offspring with normal fertility. The present results indicate that GnRH agonist treatment achieves a blockade of sexual maturation and that following cessation of treatment, normal pituitary-gonadal functions resume, with apparently normal fertility and normal offspring.

Animals↗

PubMed1989

Characteristics and distribution of receptors for [D-TRP6]-luteinizing hormone-releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer.

Binding capacities and apparent dissociation constants of receptors for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH), somatostatin (SS-14), epidermal growth factor (EGF), and estrogen and progesterone were determined in 500 breast cancer specimens using multipoint assays. Specific binding sites greater than 10 fmol/mg cytosol protein for estrogen were found in 408 carcinomas (81.6%), and for progesterone in 340 specimens (68%). High affinity EGF receptors were present in membrane preparations from 335 samples (67%). In 260 of 500 samples (52%), two classes of [D-Trp6]-LH-RH membrane receptor sites were also detected, one class showing high affinity and low capacity, and the other class showing low affinity and high capacity; 178 biopsy samples (35.6%) exhibited binding sites for SS-14. Statistically significant inverse correlations were found between the binding capacities of estrogen and EGF receptors as well as between Bmax of progesterone and EGF receptors. Significant positive correlations were demonstrated between binding capacities of estrogen and progesterone and between Bmax of high affinity and low affinity binding sites of [D-Trp6]-LH-RH receptors. However, no correlation was found between the dissociation constants of different receptor sites in human breast cancer specimens. These results demonstrate that numerous human breast cancers, in addition to receptors for estrogen and progesterone, also show binding sites for EGF, [D-Trp6]-LH-RH and SS-14. The methods described herein permit a routine quantification of receptor sites for [D-Trp6]-LH-RH, SS-14, and EGF in membrane preparations of biopsy samples of breast cancer and can be used in conjunction with the determination of estrogen and progesterone receptors in nuclear-cytosolic extracts. The simultaneous measurements using a microanalytic approach allow the determination of peptide and steroid hormone receptors that might be involved in the response mechanisms of human breast cancer. It should be possible to correlate the levels of these receptors with clinical parameters to better identify endocrine-responsive neoplasms. This approach might be useful to guide a rational hormonal therapy in women with breast cancer.

Adult↗

PubMed1986

Sonographic monitoring of LHRH analogue therapy in idiopathic precocious puberty in young girls.

Precocious puberty in young girls is defined as the development of secondary sexual characteristics and gonadal growth before 8 years of age. Approximately 60% of isosexual precocious development in girls has no organic cause and is termed idiopathic precocious puberty. Thirteen young girls with idiopathic precocious puberty were treated with LHRH analogue under a well-established protocol. Pelvic ultrasound was added to the protocol to examine ultrasound's role in supplying a morphologic parameter of suppression of the pubertal process. Initially, 11 patients had ovarian volumes greater than normal, and ovarian cysts measuring 0.5 cm to 4 cm in diameter were identified in seven patients. All 13 patients had enlarged pretreatment uteri greater than 3 cm in length. Eleven of these patients had a pubertal or adult uterine configuration. After 1 year of therapy, 11 patients had normal prepubertal ovarian volumes, and 12 of 13 patients had a decrease in ovarian volume. No demonstrable cysts were present at 1 year. Eleven had a reduction in uterine length. Nine of the 11 patients with a pubertal uterine configuration reverted to a more prepubertal-like morphology. The sonographic morphologic changes correlated well with laboratory and clinical data indicating suppression of the hypothalamic-pituitary-gonadal axis.

Child↗

PubMed2005

Transdermal iontophoretic delivery of triptorelin in vitro.

The feasibility of delivering triptorelin ([D-Trp6]LHRH) by transdermal iontophoresis was evaluated in vitro. Peptide electrotransport at different current densities and donor concentrations was measured across porcine ear skin. The concomitant delivery of an electroosmotic marker enabled calculation of the respective contributions of electromigration (EM) and electroosmosis (EO) to iontophoretic delivery. At a given concentration (3 mM), a threefold increase in current density produced a corresponding increase in the cumulative amount of peptide present in the receptor compartment. Conversely, doubling the concentration to 6 mM produced a twofold reduction in the amount of peptide delivered, partly due to a concentration-dependent inhibition of EO. EM was revealed to be the predominant transport mechanism, accounting for 80% of overall delivery. Finally, despite the inhibition of EO, the results indicate that application of an iontophoretic current of 0.8 mA over a relatively small contact area (4 cm2) would provide a delivery rate of 36 microg/h, largely sufficient for therapeutic requirements.

Acetaminophen↗

PubMed2003

Variation in chromogranin A serum levels during intermittent versus continuous androgen deprivation therapy for prostate adenocarcinoma.

OBJECTIVES: It has been hypothesized that continuous androgen-suppression therapy produces hyperactivation of neuroendocrine (NE) cells and an increase in chromogranin A (CgA) in prostate carcinoma (PC). The aim of this study was to verify whether the intermittent administration of androgen deprivation (IAD) reduces the risk of CgA increase in PC cases treated with complete androgen deprivation (CAD). MATERIALS AND METHODS: We analyzed changes in serum CgA levels in patients with PC who successfully responded to the first 24 months of IAD versus continuous CAD therapy. Two different populations were analyzed: Type 1 = pT3pN0M0 prostate cancers with biochemical (PSA) progression after RRP; Type 2 = metastatic PC directly submitted to CAD. Cases in Type 1 and Type 2 population were randomly assigned to IAD versus continuous CAD therapy. Forty cases each in Type 1 and Type 2 population were included in the analysis. At 1, 3, 6, 12, 18, 24 months of IAD versus continuous therapy, serum levels of CgA compared to PSA levels were analyzed. RESULTS: In population Type 1 and Type 2, in the group of cases continuously treated with CAD (Group 2), there was a significant trend to increase for CgA levels from baseline to 24 months of therapy. On the contrary, no significant variations were found in cases treated with IAD (Group 1). Either in population Type 1 or Type 2, at 12- and 24-month follow-up, mean and median serum levels of CgA were significantly (P < 0.005) lower in Group 1 than in Group 2. CONCLUSIONS: The present study represents the first evidence in the literature that the intermittent administration of CAD therapy significantly reduces the increase in serum CgA levels during CAD therapy.

Adenocarcinoma↗

PubMed2006

Inhibition of human experimental prostate cancers by a targeted cytotoxic luteinizing hormone-releasing hormone analog AN-207.

BACKGROUND: Receptors for luteinizing hormone-releasing hormone (LHRH) on human prostate cancers can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, which consists of superactive doxorubicin derivative 2-pyrrolino doxorubicin (AN-201) linked to carrier [D-Lys6] LHRH. METHODS: The effects of AN-207 and AN-201 were investigated in DU-145 androgen independent and LuCaP-35 androgen sensitive human prostate cancers xenografted into nude mice. Toxicity was evaluated by survival rates, changes in body weights, and leukocyte counts. LHRH receptors on DU-145 and LuCaP-35 tumors were evaluated by radioreceptor assays and RT-PCR. The effects on apoptosis and cell proliferation were investigated by histology and evaluation of apoptotic oncogenes Bcl-2 and Bax by Western Blot analysis. RESULTS: AN-207 inhibited growth of DU-145 tumors significantly by 75% (P < 0.01) and LuCaP-35 human prostate cancers by 80% (P < 0.01), and was less toxic than AN-201. Receptors for LHRH were expressed on DU-145 and LuCaP-35 tumors. Blockade of LHRH receptors with LHRH agonist Triptorelin nullified the effects of AN-207. Treatment with AN-207, but not with AN-201, decreased Bcl-2/Bax ratio in DU-145 tumors and Bcl-2 in LuCaP-35 tumors indicating an increase in apoptotic activity. AN-207, but not AN-201, decreased cell proliferation in both models. CONCLUSIONS: Targeted chemotherapy with AN-207 could be considered for treatment of advanced prostate cancer.

Androgens↗

PubMed1982

Effect of chronic administration of a highly potent LHRH agonist on prostate size and secretory function in geriatric dogs.

Four geriatric male dogs of mixed breed were selected for study on the basis of palpable prostatic hyperplasia. Testosterone levels were determined by radioimmunoassay on plasma samples collected three times weekly. Prostate size was determined from lateral pneumocystograms taken at weekly intervals. Prostatic secretion was followed by ejaculating the dogs at weekly intervals. Two dogs were implanted with 125 micrograms/kg of pelleted D-Trp6-LHRH ethylamide (LHRH analog) and two were sham implanted. The pellets were removed 71 days later. Three months after the removal, one previously treated dog was sham implanted and one previously sham implanted dog was implanted with 170 micrograms/kg of pelleted analog. In each case, following analog implantation, plasma testosterone levels were elevated for up to 7 days, then declined precipitously, and were then maintained at less than 0.02 ng/ml for a prolonged period. Plasma testosterone levels returned to the pretreatment range 44 and 58 days after implantation, respectively, in two dogs, but remained low through the 60 days studied in the third. The radiographs in one treated animal were of insufficient quality for analysis. In the remaining two treated animals, prostate size progressively declined following implantation, after about a 2 wk lag time. In one animal the prostate dimensions reached a nadir of 40% of pretreatment values at five wk after implantation. In the other treated animal the prostate regressed to a position within the pelvic brim, a state resembling that seen in young dogs, and so the dimensions could not be accurately determined. After plasma testosterone levels reverted to pretreatment values, prostate dimensions slowly but progressively increased. A decline in ejaculate volume paralleled the decline in plasma testosterone and prostate size until the fifth week after implantation from when no ejaculate could be obtained. The data suggests that LHRH agonists may have utility in the therapy of hormone-responsive prostatic pathologies.

Animals↗

PubMed1983

Inhibition of prostate tumors by agonistic and antagonistic analogs of LH-RH.

We have compared the effects of chronic administration of D-Trp6-LH-RH, a superactive agonist of LH-RH, and a potent antagonist, (NAc-p-Cl-D-Phe1,2,D-Trp3,D-Arg6,D-Ala10)LH-RH, on male Copenhagen F-1 rats bearing the Dunning R-3327H prostate adenocarcinoma. Treatment with 25 micrograms of D-Trp6-LH-RH bid for 21 days decreased the weights of the ventral prostate, testes, and adrenals, but had no effect on the weight of the anterior pituitary gland. Administration of similar doses of the antagonist reduced the weight of the ventral prostate, anterior pituitary gland, and adrenals, but did not change the weight of the testes. Both the agonist and antagonist greatly and significantly reduced tumor weight and volume as compared to controls. Serum LH, prolactin, and testosterone levels in Copenhagen F-1 rats bearing Dunning tumors were significantly decreased after treatment with D-Trp6-LH-RH as well as the antagonist. The inhibition of rat prostate tumors achieved with D-Trp6-LH-RH and the antagonistic analog raised the possibility that these compounds could be used clinically in the treatment of prostate carcinoma and other endocrine-dependent neoplasias. The antagonistic analogs have not yet been tried clinically on a chronic basis. However, the data accumulated so far from clinical trials in men with prostate carcinoma suggest that D-Trp6-LH-RH and other LH-RH agonists can be used for an effective therapy which avoids the side effects of estrogen and the pyschological impact of castration.

Animals↗

PubMed1984

Endogenous phosphorylation in Dunning prostate tumors of rats treated with LH-RH analogues.

We investigated phosphorylation in Dunning R-3327H prostate tumor tissue of untreated rats, and rats treated with the agonist D-Trp6-LH-RH and antagonist N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10-LH-RH. The total phosphorylation was significantly higher in Dunning tumors than in normal ventral and dorsal prostate. Incorporation of 32P into tumor tissue of rats treated with D-Trp6-LH-RH was significantly lower than in tumors from untreated animals. The tumor regression produced by LH-RH agonist appeared to be linked with changes in the pattern of tumor protein phosphorylation. Although inhibition of tumor growth also occurred after administration of the LH-RH antagonist, no significant changes in phosphorylation were observed. The dissimilarity of effects of the agonists and the antagonists on protein phosphorylation in rat prostate tumors may be related to the differences in the mechanisms of action of these two types of LH-RH analogues.

Animals↗

PubMed1985

Investigation of the combination of the agonist D-Trp-6-LH-RH and the antiandrogen flutamide in the treatment of Dunning R-3327H prostate cancer model.

The therapy for the treatment of prostate cancer and other sex-steroid-dependent tumors based on agonists of LH-RH has been made more practical and efficacious by the development of a long-acting formulation of microcapsules of D-Trp-6-LH-RH for controlled release. Antiandrogens, which neutralize the effect of endogenous androgens, have been used also in the management of prostate cancer in man. The effects of a simultaneous administration of the antiandrogen flutamide and microcapsules of the agonist D-Trp-6-LH-RH were studied in the Dunning R-3327H rat prostate adenocarcinoma model to determine whether the combination of these two drugs might inhibit tumor growth more effectively than single agents. Microcapsules of D-Trp-6-LH-RH, calculated to release a controlled dose of 25 micrograms/day for a period of 30 days were injected intramuscularly once a month. Flutamide was administered SC at a daily dose of 25 mg/kg. The therapy was started 100 days after the tumor transplantation and continued for 60 days. Tumor weights and volumes were significantly reduced in rats treated with microcapsules or flutamide alone, but the former drug inhibited tumor growth more than the latter. The combined treatment of flutamide and microcapsules significantly decreased tumor weight and volume, but did not exert a synergistic effect on tumor growth, the reduction being smaller for the combination than for the microcapsules alone. There was a significant elevation of serum testosterone, LH, and prolactin in rats treated with flutamide. On the other hand, in rats given microcapsules of D-Trp-6-LH-RH, testosterone fell to castration levels within 7 days and remained at nondetectable values, serum LH and prolactin levels being also suppressed in this group. The combined administration of microcapsules and flutamide also significantly decreased serum testosterone to nondetectable levels by day 7 and suppressed serum LH and prolactin. Our findings raise doubts of whether the daily administration of the combination of LH-RH agonist with an antiandrogen offers an advantage over the use of microcapsules of an agonist like D-Trp-6-LH-RH alone in the treatment of prostatic carcinoma.

Anilides↗

PubMed1985

Treatment of advanced prostatic carcinoma with D-Trp-6-LH-RH.

Twenty patients with stage D2 prostatic carcinoma were treated for up to 18 months with D-Trp-6-LH-RH. Results of more than 3 months of treatment on these 20 patients are reported. The analog was given SC once daily at a dose of 1,000 micrograms/day. All patients had bone pain and high levels of acid and alkaline phosphatase. After the first week of D-Trp-6-LH-RH administration, major decreases in bone pain and reversal of the signs of prostatism were observed. Acid phosphatase gradually fell, achieving normal values after 12 weeks. Initial plasma testosterone was within normal limits, but during treatment with D-Trp-6-LH-RH it fell to castration levels. Resting values of PRL, GH, TSH, and cortisol did not show significant changes. After TRH, TSH increased in five patients, but five did not respond. However, at 2 and 4 months, all patients released TSH in response to TRH. Two patients died during the treatment with D-Trp-6-LH-RH despite initial subjective responses and decreases in testosterone levels. The rise in acid phosphatase levels in these two patients was accompanied by a general deterioration, suggesting that they had androgen-independent cancer. One patient who developed progressive hepatic, bone, and pulmonary metastases in spite of previous orchiectomy was also treated with the analog. Three months later his acid phosphatase levels were within normal values, and partial regression of metastases was observed. These results demonstrate that D-Trp-6-LH-RH and other LH-RH agonists can be used as an effective endocrine therapy for advanced prostate carcinoma, thereby avoiding the side effects of estrogens or the psychological impact of surgical castration.

Acid Phosphatase↗

PubMed1986

Persistent blockade of the pituitary-gonadal axis in patients with prostatic carcinoma during chronic administration of D-Trp-6-LH-RH.

Forty patients with stage D2 prostatic carcinoma were treated for up to 30 months with D-Trp-6-LH-RH. The analog was given s.c. once daily at a dose of 1 mg/day for the first 7 days. Subsequently, the dose was reduced to 100 micrograms/day. In follow-up studies, 30 men continued this therapy for up to 24 months. Blood samples were taken before the injection of the analog and 1, 2, 4, and 6 hours later. Serum LH, FSH, and testosterone levels were measured by RIA every month for 2 years. The initial administration of 1 mg D-Trp-6-LH-RH caused a marked elevation of LH and FSH, which lasted more than 24 hours. However, 1 month later and throughout the therapy, the basal values of LH and FSH were below the normal range and no increase in serum gonadotropins levels was obtained after administration of the analog. Initial plasma testosterone was within normal limits, but during treatment with D-Trp-6-LH-RH it fell to castration levels, and no increases were seen during the 6 hours following the injection of the analog. These results show that chronic administration of D-Trp-6-LH-RH, at the doses used, blocks the pituitary-gonadal axis and that the escape phenomenon from the effects of the LH-RH agonists-induced blockade does not occur under our conditions in contrast to observations of Kerle et al with the I.C.I. Analog 118630 (8). The accumulated results reinforce the view that long-term therapy with agonists of LH-RH is the preferred alternative to surgical castration or therapy with estrogens in men with metastatic prostate cancer.

Acid Phosphatase↗

PubMed1986

Phase II trial with D-Trp-6-LH-RH in prostatic carcinoma: comparison with other hormonal agents.

Various approaches to hormonal treatment of prostate carcinoma are discussed. Eighty-one patients with prostatic carcinoma, eight with stage B, nine with stage C, and 64 with stage D disease, were treated subcutaneously daily for 3 months with the LH-RH agonist D-Trp-6-LH-RH (Decapeptyl) in order to evaluate the incidence of remissions according to WHO recommendations for oncologic trials. The findings were compared to those obtained with other hormonal therapies of prostatic carcinoma according to the statistical method of "expected response rate" as adapted by Lee and Wesley for phase II trials. Treatment with D-Trp-6-LH-RH greatly reduced serum LH and testosterone levels without raising serum prolactin. After 1-2 weeks of therapy, there was relief of subjective symptoms and a reversal of the signs of prostatism as well as a marked decrease in bone pain. At 90 days 52 patients had complete relief of prostatism and 21 had only mild signs and symptoms. Seventy patients were experiencing no bone pain and an additional six had only mild pain. Prostatic size, evaluated by rectal examination and transabdominal ultrasonography, reverted to normal in 26.4% of patients (complete remission) and was reduced by more than 50% in an additional 17.6% (partial remission), the overall rate of complete plus partial regression of prostatic enlargement being 44%. Scans showed a major improvement of bone lesions in 14.8% of cases. This response increased to 37% after more than 6 months of follow-up. Prostatic acid phosphatase levels were decreased by more than 50% in 61% of the patients, but this test appears to be a less valid marker than the lipid-associated sialic acid (LASA). The increase in LASA before treatment and a reduction after treatment can frequently be correlated with the objective volume of the neoplasms. No flare-up of the disease was encountered, and there were no side effects except for impotence. Statistical analyses of results by the method of Lee and Wesley indicated that the incidence of complete and partial regression (CR and PR) observed with D-Trp-6-LH-RH was not significantly different from that recorded in previous studies for another LH-RH analog, Buserelin. However, CR and PR obtained with D-Trp-6-LH-RH (44%) were significantly higher than with subcapsular orchiectomy (22%). Hormonal effects and some other actions of D-Trp-6-LH-RH were compared and contrasted with those produced by castration, estrogens, antiandrogens, and progestogens.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗