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PubMed1987

Radioimmunoassay in blood plasma of arginine esterase: the major secretory product of dog prostate.

We have developed a radioimmunoassay to determine serum levels of arginine esterase, the major secretory product of the canine prostate. Although the antibodies recognized other related proteins in immunoblotting conditions, particularly in the pancreas, the radioimmunoassay appeared specific for arginine esterase of prostatic origin and reacted only slightly or not at all with cytosolic proteins from salivary glands, liver, skeletal muscles, and kidney. In serum samples, the sensitivity limit of the assay was about 2.5 ng per ml. The interassay and intraassay variations for serum samples that contained concentrations of arginine esterase ranging from 6 to 21 ng per ml were, respectively, 14% and 24%. Sera from 30 adult males and 14 adult females contained, respectively, 71 +/- 9 and 5.3 +/- 0.4 ng per ml. In a group of 12 dogs treated daily for 36-39 days with 50 micrograms of D-Trp6-luteinizing hormone-releasing hormone ethylamide, the concentrations of arginine esterase in the serum decreased progressively and became identical with those observed in the females. These results constitute the first evidence for the presence of a serum marker of the normal prostate in an experimental model. It should be particularly useful to test the effects of various agents on the prostate.

Animals↗

PubMed1987

Histological findings in the rat prostate cancer model during treatment with a luteinizing hormone-releasing hormone agonist and novantrone.

Morphological changes produced by the treatment with the D-tryptophan-6 analog of luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) and mitoxantrone (novantrone) were studied in the Dunning R3327H rat prostate cancer model. Microcapsules of D-Trp-6-LH-RH, calculated to release a controlled dose of 25 micrograms/day, were injected intramuscularly once a month. Novantrone (0.25 mg/kg body weight) was injected intravenously once every 3 weeks. The pathology of tumors was studied in two experiments. In the first experiment, the treatment was started 135 days after tumor transplantation, and the therapy was continued for 105 days. In the second experiment, the treatment was initiated 45 days after tumor transplantation, and was carried on for 70 days. The rats were divided into four groups: 1) untreated control, 2) microcapsule-injected, 3) novantrone-injected, and 4) combination of microcapsules and novantrone-injected. In both experiments, similar results were obtained, which included significant reduction in the tumor volume and weight, a very striking decrease in the number of epithelial tumoral cells with atrophy of the glandular epithelium, and an increase in the stromal connective tissue. All these changes were more prominent in the group treated with the combination of microcapsules and novantrone than in the groups treated with microcapsules or novantrone alone. Pathological results support the view that combined therapy may be more efficacious than the treatment with single agents.

Adenocarcinoma↗

PubMed1987

Long-term results with a long-acting formulation of D-TRP-6 LH-RH in patients with prostate cancer: an Italian prostatic cancer project (P.O.N.CA.P.) study.

Ninety-five patients with stage C (C1 + C2) or D (D1 + D2) prostatic carcinoma were treated with the depot formulation of D-TRP-6 LH-RH ("Decapeptyl") for up to 33 months. Serum testosterone (T) levels were significantly reduced to castration levels within 4 weeks and maintained persistently low. Similarly, LH levels were decreased, although they remained in the normal range. Stimulation tests with either Gn-RH or HCG in course of treatment showed the achievement of a complete pituitary desensitization and almost a complete down-regulation of testicular LH receptors. Of 88 patients evaluable for response, about one-half showed an objective response. In most cases, subjective improvement with relief of bone pain and/or urinary symptoms was obtained without major side effects. These results indicate that the depot formulation of D-TRP-6 LH-RH offers an effective therapeutic alternative for patients with advanced prostatic cancer.

Acid Phosphatase↗

PubMed1988

Plasma levels of hydroxy-flutamide in patients with prostatic cancer receiving the combined hormonal therapy: an LHRH agonist and flutamide.

The present study describes a method for the measurement of the plasma levels of hydroxy-flutamide (Flu-OH), the biologically active and main circulating metabolite of flutamide. We have observed that two to four hours after oral administration of 250 mg of flutamide to healthy young men, as well as to patients with prostate cancer, the plasma concentration of Flu-OH reaches a peak at approximately 1.7 microM. The plasma concentration of Flu-OH measured at months 6, 12, and 18 of treatment shows a minimal basal level of 3.4 microM with a maximal increase at 6.8 to 8.5 microM at 2 to 4 hours. Since the serum levels of testosterone in these patients are approximately 1 nM, the levels of the active antiandrogen are at a 5000- to 10000-fold excess. However, due to the low affinity of the antiandrogen for the androgen receptor, it is extremely important to maintain this concentration of the antiandrogen in plasma constant.

Adult↗

PubMed1988

Histologic changes in the rat prostate cancer model after treatment with somatostatin analogs and D-Trp-6-LH-RH.

Histopathologic changes produced during the treatment of Dunning R3327 prostate cancer with new superactive somatostatin analogs (RC-121 and RC-160) and D-Trp-6 analog of luteinizing hormone-releasing hormone agonist (D-Trp-6-LH-RH) were studied. A significant reduction of the tumor weight could be observed in all treated groups, but the greatest decrease in the tumor volume was seen in the groups receiving the combination of the somatostatin analog and D-Trp-6-LH-RH. Histologically, the treatments resulted in a loss of the tumorous glandular elements and the proliferation of the stromal cells. In the tumors treated with somatostatin analogs, the amount of connective tissue was greatly increased and was accompanied by the appearance of thick collagenous fibers. In the D-Trp-6-LH-RH treated groups, regressive changes in the epithelium were seen in addition to the proliferation of connective tissue. The greatest histologic improvement was observed in the group treated with the combination of RC-160 and D-Trp-6-LH-RH. This histopathologic evaluation clearly supports our contention that superactive analogs of somatostatin greatly potentiate the inhibitory effect of D-Trp-6-LH-RH on the growth of Dunning prostate tumors and may improve the clinical response in patients with prostate cancer.

Adenocarcinoma↗

PubMed1988

Prolactin and luteinizing hormone-releasing hormone receptors in human benign prostatic hyperplasia and prostate cancer.

Using a sensitive micromethod for the determination of prolactin (PRL) binding sites based on 125I-human PRL ligand, PRL receptor levels in specimens of benign prostatic hyperplasia (BPH) and human prostate cancer were estimated by the one-point assay system. Ten of 19 BPH specimens (53%), showed significant PRL binding, four being in the 9-12 fmol/mg range. All ten of these cases had an histological diagnosis of nodular glandular hyperplasia. Of ten adenocarcinomas examined, four samples (40%) exhibited positive PRL binding, the highest receptor levels being 10.2 fmol/mg protein. To characterize the receptors from BPH membranes, samples were then separately pooled according to the results obtained in one-point assays. In the PRL-negative pool no displacement could be detected. In the PRL-positive pool, the Scatchard analysis revealed one class of receptors with an average affinity Kd = 1.1 X 10(-9) M and capacity Bmax = 287 fmol/mg protein. In the prostate cancer specimens, luteinizing hormone-releasing hormone receptors with a high affinity and a low capacity were also found. The results indicate the presence of prolactin receptors in prostate cancer and in BPH. The clinical implications of such findings are not clear, but it is possible that a certain proportion of BPH and prostate cancers might be in part PRL dependent. Further studies are necessary to ascertain this hypothesis in an attempt to improve the treatment of BPH and prostate cancer.

Gonadotropin-Releasing Hormone↗

PubMed1989

Inhibition of the pituitary-gonadal axis by a single intramuscular administration of D-Trp-6-LH-RH (decapeptyl) in a sustained-release formulation in patients with prostatic carcinoma.

For the past 6 years we used daily injection of luteinizing hormone-releasing hormone (LH-RH) agonists to treat patients with advanced prostate carcinoma. In this study we determined the hormonal response of the pituitary-testicular axis over a 2-month period and evaluated the safety and tolerance of the single intramuscular administration of sustained-release formulations of D-Trp-6-LH-RH microcapsules designed to release 50, 100, or 200 micrograms/day for over 1 month. Serum levels of LH, testosterone, and D-Trp-6-LH-RH were measured by RIA for up to 60 days in 10 patients with advanced prostatic carcinoma who had not received any previous drug therapy. After the administration of the microcapsules there was a biphasic increase in D-Trp-6-LH-RH serum levels. The maximal peak was obtained between 1 and 3 hr, and a second peak occurred between weeks 4 and 6. LH levels increased initially, with a maximal peak at 60 min, and elevated serum LH values persisted for more than 24 hr. LH levels began to fall on the second day, reaching subnormal values after 1 week. Serum testosterone rose during the first week and fell subsequently to less than 100 ng/dl. A rebound in LH and testosterone was seen about the 50th day after the microcapsule administration. Following the first week of therapy, we observed in all patients a significant decrease in bone pain, improvement in urinary flow obstruction, and a reversal of the signs of prostatism. No side effects were observed, and acceptance of the microcapsules was very good. Our results show that a single dose of D-Trp-6-LH-RH microcapsules suppresses of the pituitary-testicular axis for at least 50 days. D-Trp-6-LH-RH microcapsules facilitate the treatment and should lead to an improvement in the therapeutic response.

Acid Phosphatase↗

PubMed1992

Blockade of the LH response induced by the agonist D-Trp-6-LHRH in rats by a highly potent LH-RH antagonist SB-75.

During treatment of prostate cancer patients with luteinizing hormone-releasing hormone agonist, a transient LH and sex steroid release, which precedes the secretion blockade, may result in a flare-up of the disease, whereas the antagonists induce an immediate suppression. The administration of the modern, superactive LHRH antagonist SB-75 before or together with the agonist D-Trp-6-LHRH should prevent the "flare-up" phenomena. In order to demonstrate that the LHRH antagonist can prevent the initial stimulation of gonadotropins in response to LHRH agonists, groups of 5-7 male rats were injected s.c. with the antagonist SB-75 in doses in 100, 500, and 1,000 micrograms/rat 1 hour prior to or 1, 2, and 3 days before administration of D-Trp-6-LHRH agonist (50 micrograms/rat). Supraphysiological doses of the agonist were used in order to obtain prolonged stimulation of LH release, which was necessary to study the duration and the extent of LH release inhibition. Blood samples were taken before and 2, 6, 24, 48, and 72 hours after D-Trp-6-LHRH stimulation for measurement of LH levels. The administration of SB-75 in doses of 500 and 1,000 micrograms/rat 3 days prior to administration of the agonist significantly lowered LH response (P less than 0.01), as compared to animals injected with D-Trp-6-LHRH alone. The D-Trp-6-LHRH-stimulated LH secretion was markedly more suppressed by all 3 doses of the antagonist in rats pretreated with SB-75 2 days prior to the stimulation with the agonist. An even greater reduction in LH response could be observed in rats injected with SB-75 1 day prior to the agonist, the magnitude of LH response being decreased by 75% with 500 micrograms/rat SB-75 and by 90% with 1 mg/rat SB-75. The LH response was virtually abolished when the antagonist, SB-75 was given in doses of 500 or 1,000 micrograms/rat 1 hour prior to the D-Trp-6-LHRH injection. Under these conditions, the agonist-induced LH and testosterone secretion was completely suppressed during the whole period of the experiment. The antagonist to agonist dose ratio of 2 to 1 produced a 90% decrease in the LH response to D-Trp-6-LHRH at 2 hours and 75% at 5 hours after agonist administration. The effects of LHRH decapeptide itself (500 micrograms/rat) on LH secretion could be totally suppressed by an injection of 50 micrograms/rat of SB-75 1 hour beforehand.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Inhibition of growth of PC-82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC-3095 or combination of agonist [D-Trp6]-luteinizing hormone-releasing hormone and somatostatin analog RC-160.

The effects of treatment with a bombesin receptor antagonist [D-Tpi6, Leu13 psi (CH2NH) Leu14]BN(6-14)(RC-3095) and the combination of an agonist of luteinizing hormone-releasing hormone [D-Trp6]-LH-RH and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val- Cys-Trp-NH2 (RC-160) were studied in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC-3095 and the combination of [D-Trp6]-LH-RH and RC-160 caused a greater inhibition of tumor growth than [D-Trp6]-LH-RH or RC-160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC-160 and [D-Trp6]-LH-RH. Serum prostatic-specific antigen levels were greatly decreased, and insulin-like growth factor I (IGF-I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D-Trp6]-LH-RH, epidermal growth factor (EGF), IGF-I, and somatostatin (SS-14) were found in the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with the bombesin antagonist or RC-160. Combination of LH-RH agonists with somatostatin analog RC-160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC-3095 inhibits the growth of PC-82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.

Amino Acid Sequence↗

PubMed1994

Effect of the nonsteroidal antiandrogen nilutamide on adrenal androgen secretion.

The nonsteroidal androgen-receptor antagonist nilutamide has previously been shown to inhibit adrenal androgen steroidogenesis in patients with prostatic carcinoma treated in combination with an LHRH agonist. In order to understand better the mechanisms subserving this observation, we have studied the effects of nilutamide alone on the serum concentrations of androstenedione (A), dehydroepiandrosterone (DHEA), and DHEA-sulphate (DHEA-S) in 12 patients with prostatic cancer and compared them with those achieved in 21 patients treated with the agonist D-Trp-6-LHRH. In addition, the adrenocorticotropic hormone (ACTH)-stimulated adrenal response and the thyrotropin releasing hormone (TRH)-stimulated prolactin (PRL) response observed in the patients treated with nilutamide were compared with a control group of healthy age-matched controls. No significant variation in the basal concentrations of adrenal androgens occurred either within or between both treatment groups. In response to ACTH, a decreased 17-alpha hydroxyprogesterone (17-OHP) accumulation and an augmented A/17-OHP ratio were observed in the antiandrogen group (P < 0.05 for both), suggesting the partial removal of the 17,20 lyase block which was distinctive of the untreated controls, while no significant difference was found for other steroids. Basal PRL levels were not affected by the antiandrogen, but the response to TRH was increased. We conclude that no significant inhibition of adrenal androgen secretion occurs after nilutamide or LHRH agonist treatment. Rather, administration of the antiandrogen alone may partially remove the physiological decrease in adrenal androgen secretion observed in the elderly.

Adrenal Glands↗

PubMed1994

Metastatic prostate cancer pulmonary nodules: beneficial effects of combination therapy and subsequent withdrawal of flutamide.

A case is presented of a middle-aged man suffering from stage D2 prostate cancer with pulmonary metastases who responded favorably, first, to endocrine combination therapy with the antiandrogen flutamide and an LHRH agonist for 5.5 years, and, second, to the subsequent withdrawal of Flutamide at the time of the progression of the disease. This case has several exceptional features: absence of bone metastases, pulmonary metastatic nodules characterized as focal neuroendocrine differentiation, and a positive response to antiandrogen withdrawal upon relapse of metastases after initial positive response. The concept of escape to androgen blockade and development of androgenic hypersensitivity is discussed.

Acid Phosphatase↗

PubMed2001

Investigation of synthetic peptide hormones by liquid chromatography coupled to pneumatically assisted electrospray ionization mass spectrometry: analysis of a synthesis crude of peptide triptorelin.

Triptorelin, a synthetic peptide hormone used in the treatment of prostate cancer by means of reduction in the action of male hormone testosterone, is studied here. The synthetic procedure commonly results in unwanted side products that require extensive purification and characterization of the synthesis mixture. The chromatographic separation of triptorelin from the crude mixture was developed by applying the linear solvation energy relationship (LSER) methodology previously developed, to optimize the composition of the mobile phase in order to avoid lengthy empirical optimization procedures. Electrospray ionization mass spectrometry coupled to liquid chromatography (LC/ES-MS) was used to obtain reliable information on the inevitable side products. The knowledge of the identity of these impurities allows fast optimization of the synthetic procedure and also the therapeutic use of triptorelin peptide hormone.

Amino Acid Sequence↗

PubMed1993

In vivo effects of oLH and LHRH-analog on sex reversal and plasma sex steroid profiles in the female Monopterus albus.

The effects of ovine-luteinizing hormone (oLH) or a synthetic analog of luteinizing hormone-releasing hormone, Des-Gly10[S-Ala6]-LHRH ethylamide acetate salt (LHRH-A), on the female phase of the protogynous Monopterus albus were investigated, and the plasma levels of androstenedione (Ad), testosterone (T), 11-oxotestosterone (KT), 11 beta-hydroxytestosterone (OHT), 17 beta-estradiol (E2) and progesterone were determined. In the postspawning stage, oLH induced precocious sex reversal in the gonad from female to male and increased plasma levels of Ad, T, KT and OHT. However, such oLH effects in M. albus females were slight at the early prespawning stage, and no significant signs of precocious sex reversal were found either in gonadal structure or in plasma hormones as those in postspawning treatment. After LHRH-A treatment of M. albus females in both postspawning and early prespawning stages, the gonadal structure remained "female type" with no sign of proliferation of either Leydig cells or male germ cells. The plasma levels of E2 were greatly increased after the treatment.

Animals↗

PubMed1998

Use of a GnRH agonist to suppress testosterone in wild male Hawaiian monk seals (Monachus schauinslandi).

A gonadotropin-releasing hormone (GnRH) agonist, d-Trp6-LHRH, was evaluated for its effectiveness in reducing circulating testosterone concentrations in wild Hawaiian monk seals (Monachus schauinslandi). Twenty-eight adult male seals were randomly divided into three groups: 10 were captured and treated with 7.5 mg of the GnRH agonist, 9 were captured but did not receive the agonist, and 9 were captured near the end of the study to serve as handling controls. Blood samples were taken from all 28 seals. From 14 to 58 days after initial capture, 8 of the treated seals and 8 of the untreated seals were recaptured and a second sample of blood was taken. For comparison, blood was also collected from 4 captive adult male seals during the same months as the field study. In the treated group, the agonist induced a significant decline in mean circulating testosterone concentrations, from 1.01 ng/ml (first sample) to 0.21 ng/ml (second sample, taken approximately 38 days later). In the untreated group, mean testosterone concentrations of the first and second samples were statistically indistinguishable (1.11 vs 1.16 ng/ml). The mean concentration of the untreated group (second sample) was also indistinguishable from the mean concentration of seals in the control group (1.16 vs 0.82 ng/ml). Also, mean testosterone concentration in the initial samples from the four captive seals was not statistically different from that of untreated wild seals (1.38 vs 1.11 ng/ml). These results suggest that (1) the GnRH agonist suppresses the production of testosterone in wild adult male Hawaiian monk seals, (2) a single handling of adult male seals does not affect their testosterone levels, and (3) testosterone concentrations in captive male seals appear to be consistent with concentrations in wild seals. Further evaluation of this GnRH agonist is necessary before it is used in the management of this endangered species, but these results suggest it may be a useful tool for reducing mortality of monk seals from adult male aggression related to reproduction and mating behavior.

Animals↗

PubMed1997

Treatment of endometrial hyperplasias with gonadotropin-releasing hormone agonists: pathological, clinical, morphometric, and DNA-cytometric data.

On the basis of the recently reported observation that gonadotropin-releasing hormone agonists (GnRH-a) can affect endometrial cell proliferation, both indirectly, through the hormonal axis, and directly, by acting on the GnRH-a receptors, we investigated how far GnRH-a can be used as a new treatment mode for endometrial hyperplasias. Forty-two women, aged 28-60 years, with histologically confirmed simple (n = 30) or complex (n = 12, 2 with atypias) hyperplasia of the endometrium were involved in the study. According to the protocol they were treated for 6 months with GnRH-a (leuprolide acetate or triptorelin), and each patient underwent uterine curettage in the third and the sixth month of treatment, and 6 and at least 12 months after cessation of the treatment, for histological examination and morphometric and DNA-cytometric evaluation of the endometrium (mean pathological follow-up, 19.2 months; mean clinical follow-up, 30.7 months). During treatment, most of the women first revealed endometrial atrophy, and, after cessation of the treatment, again an atrophic or mainly functional endometrium; in 7 women, all with initial diagnosis of simple hyperplasia, the endometrial hyperplasia reappeared, which led in all 7 cases to hysterectomy. The mean values of almost all morphometric and DNA-cytometric parameters during and after treatment showed statistically significant changes in relation to pretreatment values, indicating a decrease in the proliferative activity of the endometrial cells; the GnRH-a antiproliferative effect was still active for a long time after cessation of the therapy. Our results, based for the first time not only on histological but also on serial nuclear morphometric and DNA-cytometric examinations of the endometrial cells and on the longest follow-up time, support the view that in cases of endometrial hyperplasia, especially of complex type, the use of GnRH agonists, which decrease the proliferative tendency of endometrial cells, could represent an alternative conservative therapeutic approach, which, however, requires close monitoring of the endometrium.

Adult↗

PubMed1999

Atypical endometrial hyperplasia treatment with progestogens and gonadotropin-releasing hormone analogues: long-term follow-up.

OBJECTIVE: The aim of this study was to assess the long-term effect of gonadotropin-releasing hormone analogues (GnRH-a) in combination with high-dose progestogens in the treatment of atypical endometrial hyperplasia in selected surgical high-risk patients and in women desiring reproductive potential. We hypothesized that this therapy is effective for most couples. METHODS: In the Department of Gynecology of a university hospital, a conservative treatment was offered to a series of 22 patients with atypical endometrial hyperplasia who had a surgical or anesthetic risk history or wished to preserve their fertility potential. After informed consent, they were treated with 500 mg norethisterone acetate weekly for 3 months and 3.75 mg Triptorelin depot every month for 6 months. Three patients failed to complete the study, so the group finally consisted of 19 subjects. They were prospectively followed for 5 years by hysteroscopy and multiple selected biopsies every 6 months. RESULTS: At a 5-year follow-up, regression was noted in 16 patients (84.2%), persistence in 1 (5.1%), recurrence in 1 (5.1%), and progression in 1 (5.1%). CONCLUSION: Consistent with our hypothesis, combined treatment with progestogens and GnRH-a is an effective alternative in selected patients with atypical endometrial hyperplasia.

Adult↗

PubMed1999

Cell cycle arrest in endometrial carcinoma cells exposed to gonadotropin-releasing hormone analog.

Gonadotropin-releasing hormone (GnRH) has been shown to have an inhibitory effect on the growth of several hormone-dependent human tumors. We have treated a human endometrial cancer cell line which expresses GnRH receptor with GnRH analog, D-Trp6-LHRH, in order to study whether there are differences in cell cycle kinetic response. Flow cytometric analysis revealed that cultured carcinoma cells showed a cell cycle arrest at the G1-S transition after treatment with 10 microM D-Trp6-LHRH for 36 h. Western blot analysis showed that the level of p16 protein was obvious following 24 h of D-Trp6-LHRH treatment. These results suggest that the mechanism by which GnRH inhibits the growth of endometrial carcinoma cells may include effects on cell cycle arrest.

Endometrial Neoplasms↗

PubMed1999

Antitumor effect of GnRH agonist in epithelial ovarian cancer.

OBJECTIVE: The effects of the gonadotropin releasing hormone (GnRH) agonist (D-Trp(6)) were examined in two human ovarian cancer cell lines and in severe combined immune deficiency (SCID) mice to evaluate its potential as a cytocidal, cytostatic, or differentiating antitumor agent. METHODS: We treated the human ovarian cancer cell lines OVCAR-3 and SKOV-3 for 5 or 7 days and sex-matched SCID mice with GnRH agonist for 29 days. The antitumor effect of GnRH agonist were studied in various aspects. To confirm the antiproliferative effect, we used 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide colorimetric assay, in vitro, and a serial measurement of tumor growth in vivo. The disturbances of progression in the cell cycle and the changes of cyclin-dependent kinase 1 following treatment with GnRH agonist were evaluated with flow cytometric analysis in vitro. The induction of apoptosis following treatment with GnRH agonist was studied using in situ terminal deoxyribonucleotidyl transferase (Tdt) and further quantitated with ELISA in vitro. The presence of telomerase activity following treatment with GnRH agonist was measured by PCR-based telomeric repeat amplification protocol and ELISA detection in cell lines and xenografts in vitro and in vivo. RESULTS: Continuous exposure of cell lines and xenografts to GnRH agonist resulted in growth inhibition of cancer cells in a dose- and time-dependent manner. In cultured cells, the GnRH agonist blocked cell cycle progression in G0/G1 phase and thus reduced the number of cells in S and G2/M phases. The phenomenon of apoptosis was documented in cultured cells treated with GnRH agonist by in situ Tdt assay. The frequency of apoptotic cells in the in situ Tdt assay was 5-6% compared with control, 4-5%. Apoptosis quantified by ELISA revealed a high incidence in cultured cells treated with GnRH agonist. The activities of telomerase in cell lines and xenografts were not decreased by GnRH agonist. There were not any significant changes of expression of CA-125 by flow cytometry and of the cellular morphology observed with light microscopy. CONCLUSIONS: Our results indicate that the antiproliferative effect of GnRH agonist in epithelial ovarian cancer cells may be mainly attributed to cytostatic activities resulting in blocking of cell cycle progression in the G0/G1 phase and minimally related to the induction of apoptosis.

Animals↗