New approaches to therapy of cancers of the stomach, colon and pancreas based on peptide analogs.

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.

Hypothalamic hormones and cancer.

The use of peptide analogs for the therapy of various cancers is reviewed. Inhibition of the pituitary-gonadal axis forms the basis for oncological applications of luteinizing hormone-releasing hormone (LH-RH) agonists and antagonists, but direct effects on tumors may also play a role. Analogs of somatostatin are likewise used for treatment of various tumors. Radiolabeled somatostatin analogs have been successfully applied for the localization of tumors expressing somatostatin receptors. Studies on the role of tumoral LH-RH, growth hormone-releasing hormone (GH-RH), and bombesin/GRP and their receptors in the proliferation of various tumors are summarized, but the complete elucidation of all the mechanisms involved will require much additional work. Human tumors producing hypothalamic hormones are also discussed. Treatment of many cancers remains a major challenge, but new therapeutic modalities are being developed based on antagonists of GH-RH and bombesin, which inhibit growth factors or their receptors. Other approaches consist of the use of cytotoxic analogs of LH-RH, bombesin, and somatostatin, which can be targeted to receptors for these peptides in various cancers and their metastases. These new classes of peptide analogs should lead to a more effective treatment for various cancers.

Peptide analogs in the therapy of prostate cancer.

The use of peptide analogs in the therapy of prostate cancer is reviewed. The preferred primary treatment of advanced androgen-dependent prostate cancer is presently based on the use of depot preparations of LH-RH agonists. This treatment is likewise recommended in patients with rising PSA levels after surgery or radiotherapy. LH-RH agonists with or without antiandrogens can be also utilized prior to or following various local treatments in patients with clinically localized prostate cancer and at high risk for disease recurrence. LH-RH antagonists like Cetrorelix are in clinical trials. However, most patients with advanced prostatic carcinoma treated by any modality of androgen deprivation eventually relapse. Treatment of relapsed androgen-independent prostate cancer remains a major challenge, but new therapeutic modalities are being developed based on antagonists of growth hormone-releasing hormone (GH-RH) and bombesin, which inhibit growth factors or their receptors. Another approach consists of cytotoxic analogs of LH-RH, bombesin, and somatostatin containing doxorubicin or 2-pyrrolinodoxorubicin, which can be targeted to receptors for these peptides found in prostate cancers and their metastases. These cytotoxic analogs inhibit growth of experimental androgen-dependent or -independent prostate cancers and reduce the incidence of metastases. A rational therapy with peptide analogs could be selected on the basis of receptors present in biopsy samples. The approaches based on peptide analogs should result in a more effective treatment for prostate cancer.

Efficacy and safety of luteinizing hormone-releasing hormone antagonist cetrorelix in the treatment of symptomatic benign prostatic hyperplasia.

As the life expectancy for men increases, more cases of benign prostatic hyperplasia (BPH) will be expected. Symptomatic BPH causes morbidity and can lower the quality of life. We investigated whether short term administration of the LH-releasing hormone antagonist cetrorelix could provide an improved treatment for men with BPH. Thirteen patients with moderate to severe symptomatic BPH were treated with cetrorelix (5 mg, s.c., twice daily for 2 days followed by 1 mg/day, s.c., for 2 months). Patients were evaluated at baseline, during treatment, and up to 18 months after therapy. We determined the effects of cetrorelix on the International Prostate Symptom Score (IPSS), Quality of Life score, sexual function, prostate size, uroflowmetry, and hormonal levels. Treatment with cetrorelix produced a decline of 52.9% (P < 0.0001) in IPSS, a 46% improvement in the Quality of Life score (P < 0.001), a rapid reduction of 27% (P < 0.006) in prostatic volume, and an increase in peak urinary flow rates by 2.86 mL/s. Serum testosterone fell to castrate levels on day 2, but was inhibited only by 64-74% during maintenance therapy, and after cessation of treatment returned to normal. During long term follow-up, most patients continued to show a progressive improvement in urinary symptoms (decline in IPSS from 67% to 72% at weeks 20 and 85, respectively) and an enhancement of sexual function, and prostatic volume remained normal. Our study demonstrates that in patients with symptomatic BPH, treatment with cetrorelix is safe and produces long term improvement.

Treatment of uterine leiomyomas with luteinizing hormone-releasing hormone antagonist Cetrorelix.

The efficacy of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in the medical management of uterine leiomyomas (fibromas) was evaluated. Cetrorelix was administered to 18 pre-menopausal women with myomas with a mean age of 33.3 years, who had been candidates for hysterectomy. The initial dose of Cetrorelix was 5 mg twice daily s.c. for the first 2 days and thereafter 0.8 mg was given twice daily s.c. for at least 3 months. The mean duration of the treatment was 4.4 months. Before the therapy with Cetrorelix, the mean uterine volume, measured by ultrasonography, was 395.4 +/- 69.2 ml (range 89-1166). Sixteen patients showed a progressive reduction in uterine volume from 410.4 +/- 77.1 to a mean of 230.8 +/- 52.6 ml at 3 months. All patients became amenorrhoeic and had hot flushes. After treatment with Cetrorelix, a surgical myomectomy was performed in 12 women. One of the patients subjected to myomectomy after therapy with Cetrorelix became pregnant. These patients have been followed for up to 25 months and only in one case has the uterine volume increased after therapy. Three patients had good responses to therapy with Cetrorelix and it was decided to follow them only by observation. One patient became pregnant 2 months later. In the other patient, the uterine volume remained unchanged for the duration of the follow-up of 2 years and the third patient showed an increase after 21 months. In three patients, it was necessary to perform total hysterectomy. In 14 patients, serum concentrations of luteinizing hormone, follicle stimulating hormone and oestradiol decreased after the administration of the first dose of Cetrorelix and continued at subnormal values throughout therapy. In 15 patients who were not subjected to total hysterectomy, menstrual function returned at 1 month after cessation of treatment. Overall results support the use of Cetrorelix for the management of uterine leiomyomas.

Development and applications of luteinizing hormone-releasing hormone antagonists in the treatment of infertility: an overview.

Luteinizing hormone-releasing hormone (LHRH) plays a crucial role in controlling the ovarian cycle in women. By modification of the molecular structure of this decapeptide, analogues were synthesized with agonistic or antagonistic effects on the gonadotrophic cells of the anterior pituitary gland. The agonists, after an initial stimulatory effect ('flare up'), lead to desensitization of the gonadotrophic cells and a reduction in the number of LHRH receptors on the cell membrane ('down-regulation'), while the antagonists produce an immediate effect by competitive blockade of the LHRH receptors. After administration of LHRH antagonists, the serum levels of FSH and LH decrease within hours. Nevertheless, the adenohypophysis maintains its responsiveness to an LHRH stimulus ('pituitary response') after pretreatment with an antagonist. This different pharmacological mechanism of LHRH antagonists makes possible new approaches to ovarian stimulation and to the therapy of sex steroid dependent diseases. The premature LH surge, the main cause of cancellation during induction of superovulation in assisted reproduction technology (ART) programmes, can be abolished by short term application of an LHRH antagonist associated with a reduced human menopausal gonadotrophin (HMG) requirement for ovarian stimulation. A future approach to ART might be based on the combination of pretreatment with an LHRH antagonist and ovulation induction by native LHRH or an agonist. The severe side effects encountered with early LHRH antagonists, such as anaphylactoid reactions due to histamine release, are almost completely eliminated in modern antagonists, especially Cetrorelix which is presently used clinically in controlled phase II clinical studies.

Luteinizing hormone-releasing hormone antagonist cetrorelix as primary single therapy in patients with advanced prostatic cancer and paraplegia due to metastatic invasion of spinal cord.

OBJECTIVES: To assess the clinical response to luteinizing hormone-releasing hormone (LH-RH) antagonist cetrorelix (SB-75) in patients with advanced carcinoma of the prostate and paraplegia due to metastatic invasion of spinal cord. METHODS: Cetrorelix was given at two different dose regimens to 5 patients with prostatic cancer Stage D2 and paraplegia. Urologic and neurologic examinations, laboratory studies, radiography (myelography), and prostate ultrasonography were carried out. Prostate-specific antigen (PSA) and free testosterone were also measured. RESULTS: In all patients, the neurologic symptoms regressed. The recovery of the thermic and vibratory sensation and motility of the toes was observed. The neurologic improvement continued during the treatment and at 3 months all the patients were able to walk with the aid of a cane. In 1 patient, the myelography showed that the spinal cord compression had disappeared and prostate volume assessed by ultrasonography showed a significant decrease. The bladder function greatly improved in all 5 patients during the treatment with cetrorelix. Baseline levels of luteinizing hormone fell from 9.28 to 1.0 IU/L and those of follicle-stimulating hormone (FSH) fell from 18.28 to 12 IU/L (P < 0.05) after the first day of therapy with cetrorelix. Mean levels of free testosterone were reduced from 52.4 to 14.7 pmol/L (P < 0.005) at 12 hours and to 13.1 pmol/L (P < 0.005) 3 days after the first injection of cetrorelix. A persistent inhibition of gonadotropins and testosterone was maintained during the subsequent 3 months of therapy. The high levels of PSA gradually decreased. CONCLUSIONS: Our results show that LH-RH antagonist cetrorelix causes an immediate lowering of the serum testosterone levels in patients with prostate cancer and metastases in the spinal cord, in whom the LH-RH agonists cannot be used as single drugs because of the possibility of flare-up and appears to be appropriate for long-term therapy.

Inhibition of luteinizing hormone, follicle-stimulating hormone and sex-steroid levels in men and women with a potent antagonist analog of luteinizing hormone-releasing hormone, Cetrorelix (SB-75).

Cetrorelix (SB-75; [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10] luteinizing hormone-releasing hormone (LHRH)) is a new highly potent antagonist analog of LHRH containing the D-ureidoalkyl amino acid D-citrulline at position 6 and is free of allergenic effects. This study shows the inhibition of LH and follicle-stimulating hormone (FSH) release in normal men, postmenopausal women and patients with gonadal dysgenesis, using different doses and i.m., s.c. and i.v. routes of administration of SB-75. The mean serum levels of LH and FSH in normal men who received one single dose of 300 micrograms of SB-75 sc started to decline rapidly 1 h after its administration; the LH suppression was sustained for 14 h and that of FSH up to 24 h or longer as the samples were obtained only up to this time. The nadir for LH was reached at 14 h and that for FSH at 24 h or later after administration of the antagonist (p < 0.05). Serum levels of total and free testosterone decreased after the first hour and this inhibition was maintained for up to 14 h. The nadir for total testosterone was at 6 h and that for free testosterone was at 8 h (p < 0.001), corresponding to 56% and 60% of inhibition, respectively. In postmenopausal women, inhibition of the elevated basal serum LH and FSH levels occurred after a single injection of the antagonist analog SB-75 in doses of 75, 150, 300, 600 and 1200 micrograms using im, sc and iv routes of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses to the antagonistic analog of LH-RH (SB-75, Cetrorelix) in patients with benign prostatic hyperplasia and prostatic cancer.

Among new highly potent antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH), containing neutral hydrophilic D-ureidoalkyl amino acids such as D-Cit and D-Hci at position 6 and free of edematogenic and anaphylactoid reactions, Ac-D-Nal(2)1, D-Ph(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10 (LH-RH) (SB-75; Cetrorelix) was shown to be one of the most powerful. In this trial, we evaluated the response to 500 micrograms SB-75 given every 12 hr subcutaneously (sc) for 4 weeks in 11 patients with benign prostatic hyperplasia (BPH), and 6 weeks in 6 prostatic cancer patients (2 stage C, 4 stage D2). In patients with BPH presenting with prostatism and urinary outflow obstruction, there was a noticeable clinical improvement after the first week of SB-75 administration. This improvement continued during the course of treatment. Before therapy with SB-75, the serum levels of prostate-specific antigen (PSA) (6.73 +/- 1.46 ng/ml), acid phosphatases, total (12.67 +/- 1.15 U/l), and prostatic (2.27 +/- 0.34 U/l), were mildly elevated, but declined to normal values at 4 weeks: (2.13 +/- 0.59 ng/ml; P < 0.01), (7.68 +/- 0.89 U/l; P < 0.01), and (1.39 +/- 0.18 U/l; P < 0.01), respectively. Mean prostatic volume assessed by ultrasonography showed a significant decrease in all patients from 67.84 +/- 8.86 to 37.92 +/- 8.52 cm3; P < 0.01, which represents a reduction of 44%. In patients with prostate cancer, after the first week of therapy with SB-75, we observed a significant decrease in bone pain, relief in urinary outflow obstruction, and reversal of the signs of prostatism. Subjective improvement continued during the following weeks of treatment, so that the patients no longer needed analgesics. PSA, acid, and alkaline phosphatases gradually fell, achieving nearly normal values at 6 weeks. Initial serum testosterone levels in BPH and prostatic cancer patients were within normal limits, but during treatment with the antagonistic analog SB-75, fell to castration values. A major fall in free testosterone levels was observed after the first dose; the maximal inhibition was seen after 6-12 hr, with a simultaneous decrease in levels of both gonadotropins. Our results show that antagonist SB-75 can be safely administered for prolonged periods of time. The rapid shrinkage of the prostate and concomitant improvement in obstructive symptoms of prostatism obtained with antagonistic analog SB-75 in patients with BPH may decrease the morbidity of prostatic surgery and offer a therapeutic alternative in men who are considered poor surgical risks.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibitory effect of a highly potent antagonist of LH releasing hormone (SB-75) on the pituitary gonadal axis in the intact and castrated rat.

The biological potency of the new, highly potent antagonist [AC-D-Nal (2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10] LH-RH (SB-75) on the pituitary-gonadal system of female castrated and intact ovulating rats was tested. Administration of a single dose (50-100 micrograms/kg BW) of the antagonist SB-75 inhibited effectively the elevated gonadotrophin levels for 48 h. Pituitary LH and FSH content was not affected by SB-75 treatment. When administered in the early afternoon of the proestrus to intact cycling rats, SB-75 blocked the preovulatory LH surge as well as the primary and secondary FSH surges. However, the secondary FSH surge was not affected by SB-75 treatment when administered on the evening of proestrus suggesting its independence from the LH-RH mechanism. A group of ovariectomized rats was chronically treated with D-Trp6-LH-RH after having been pretreated by administration of a single dose of the antagonist. The initial stimulatory release of LH and FSH initiated by injection of the LH-RH agonist was significantly reduced by pretreatment with the LH-RH antagonist. We conclude that the LH-RH antagonist SB-75 may be used effectively in the field of reproductive dysfunction and endocrinological oncology and may become an invaluable physiological probe in studying the hormonal dynamics of the reproductive endocrine axis.

Comparison of GH-stimulation by GH-RH(1-29)NH2 and an agmatine29 GH-RH analog, after intravenous, subcutaneous and intranasal administration and after pulmonary inhalation in rats.

Many studies have shown that human GH-RH(1-29)NH2 possesses full intrinsic activity of GH-RH(1-44)NH2 in vitro and in vivo. This investigation was performed to evaluate the efficacy of GH-RH(1-29)NH2 given by different routes of administration in stimulating GH release in rats. In each case GH-RH(1-29)NH2 was administered intravenously, subcutaneously, intranasally and by pulmonary inhalation at two different doses to groups of seven males rats. At a dose of 150 micrograms/kg GH-RH(1-29)NH2, the magnitude of GH response was significantly higher for the pulmonary inhalation group (355 +/- 33.2 ng GH/mL) than for the subcutaneous group (246 +/- 36 ng GH/mL) or for the intranasal group (175 +/- 30 ng GH/mL). The group injected intravenously with GH-RH(1-29)NH2 at a dose of 2.5 micrograms/kg showed the highest response, GH levels reaching 877.2 +/- 115 ng/mL. A similar pattern of responses was obtained for the superactive GH-RH(1-29) agmatine29 analog, MZ-3-149, at doses that were 50 times lower. Our results indicate a high bioavailability of GH-RH(1-29)NH2 or analog MZ-3-149 administered by a convenient pulmonary inhalation route. The GH-releasing effect of GH-RH(1-29)NH2 or analog MZ-3-149 delivered by pulmonary inhalation is superior to subcutaneous and intranasal administration.

Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals.

The effects of hybrid cytotoxic LH-RH analogs, produced by linking anthraquinone or methotrexate to carrier LH-RH agonist [D-Lys6]LH-RH, were evaluated in Copenhagen-Fisher F1 rats bearing Dunning R-3327H prostate adenocarcinoma. The two cytotoxic LH-RH analogs T-98 [(D-Lys6)LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone (G-HMAQ)], and AJ-04 [(D-Lys6)LH-RH linked to methotrexate (MTX)], carrier [D-Lys6]LH-RH, or the free cytotoxic compounds MTX and G-HMAQ were administered from Alzet Osmotic minipumps for 7-8 weeks. The cytotoxic LH-RH analogs caused somewhat greater tumor growth inhibition than the carrier peptide, while anthraquinone or methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary-gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in tumors treated with AJ-04, T-98, [D-Lys6]LH-RH, or by castration than in those of controls. Serum hormone levels were lowered by both carrier peptide and cytotoxic analogs, LH being substantially depressed, and testosterone not detectable. These results and other findings indicate that LH-RH analogs containing cytotoxic radicals anthraquinone or methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic LH-RH analogs to tumors such as prostate cancer, which have receptors for LH-RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted chemotherapy, might be of practical therapeutic importance for the management of advanced prostate cancers, which eventually relapse after palliative hormonal therapy.

Somatostatin analogue RC-160 and LH-RH antagonist SB-75 inhibit growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice.

Nude mice bearing xenografts of the MIA PaCa-2 human pancreatic cancer cell line were treated with sustained-release formulations (microcapsules) of luteinizing hormone releasing hormone (LH-RH) agonist [D-Trp6]-LH-RH, somatostatin analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2), or combination of both analogues. Other groups of mice received daily subcutaneous injections of LH-RH antagonist SB-75 [Ac-D-Nal(2)',D- Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10-LH-RH] or bombesin antagonist RC-3095. At necropsy, in mice given microcapsules releasing 25 micrograms/day of [D-Trp6]-LH-RH, tumor weight and volume were decreased, but not significantly, as compared with control mice. Microcapsules of RC-160, releasing 25 micrograms/day, significantly reduced tumor volume, percentage change in tumor volume, and tumor weight. Combination of RC-160 and [D-Trp6]-LH-RH inhibited tumor growth to a somewhat greater extent than RC-160 alone. Bombesin antagonist RC-3095, at a dose of 25 micrograms/day, did not influence the growth of tumors. In mice receiving 100 micrograms/day of antagonist SB-75, there was a significant decrease in tumor weight and volume and a significant reduction in the weight of ovaries and uteri. Specific binding of [125I]RC-160 and [125I][D-Trp6]-LH-RH, but not [125I]Tyr4-bombesin, was found on MIA PaCa-2 cells in culture. [D-Trp6]-LH-RH, SB-75, and RC-160 inhibited the growth of MIA PaCa-2 cells in vitro. Neither bombesin nor RC-3095 influenced the growth of MIA PaCa-2 cells in cultures. The results indicate that the LH-RH antagonist SB-75 could be tried for treatment of pancreatic cancer. Our findings confirm the efficacy of somatostatin analogue RC-160 in inhibiting the growth of pancreatic cancers and suggest that the combination of RC-160 and agonist [D-Trp6]-LH-RH might possibly increase the therapeutic response.

Treatment of experimental DMBA induced mammary carcinoma with Cetrorelix (SB-75): a potent antagonist of luteinizing hormone-releasing hormone.

Cetrorelix, (Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10)-LHRH (SB-75) is a new highly potent antagonist of LH-RH. In the model of DMBA-induced mammary carcinoma, this antagonist was very effective in reducing tumor mass. A rapid decrease in tumor weights to levels below 0.1 g total tumor mass was achieved with 300 micrograms/kg given sc. daily for 14 days. The weights of uteri and ovaries were reduced to about 40-50% of control values. In all treated rats the estrus cycle was interrupted and the animals remained in a state of anestrus. Microscopically, the effects of Cetrorelix on the tumors were characterized by a loss of mitotic activity, marked regression with apoptosis, an increase of stroma and differentiation towards a normal mammary architecture. On the basis of a dose-response curve, a dose of 100 micrograms/kg/d of Cetrorelix was determined as sufficient for a full antitumor response. Large DMBA-tumors with total tumor mass of about 6 g could also be treated very effectively with a dose of 100 micrograms/kg/d. To achieve a complete tumor regression, the treatment had to last 34 days. After the cessation of treatment with 100 micrograms/kg/d and regrowth of the tumors the animals were treated with the agonist Decapeptyl (Trp6-LHRH) using a dose of 50 micrograms/rat/d for 14 days. Again, the tumors responded well and regressed within 10 days. The treatment with an overlapping dose schedule of Cetrorelix and Decapeptyl showed a continuous antitumor response. A transient stimulation of tumor growth by the LH-RH agonist was not observed under these experimental conditions. In ovariectomized rats bearing DMBA-tumors, treatment with Cetrorelix and estradiol, produced no tumor growth inhibition as compared to estradiol control group, indicating that there is no estrogen nullifying effect of this antagonist on tumor cells in this model. On the basis of these results, Cetrorelix is a highly effective antitumor agent in this breast cancer model, which might also be useful under clinical conditions.

Inhibition of growth of MCF-7 MIII human breast carcinoma in nude mice by treatment with agonists or antagonists of LH-RH.

Human breast carcinoma (MCF-7 MIII), which exhibits an estrogen-independent but estrogen-responsive phenotype, was xenografted in 8-9-week-old intact female athymic nude mice without estrogen supplementation. In this model, we investigated inhibitory effects of the modern luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and the agonist D-Trp6-LH-RH. The analogs were administered in the form of sustained delivery systems (microcapsules and microgranules). In the first experiment, treatment lasted 10 weeks. After 9 weeks of treatment, a significant inhibition of tumor volume was first found only in the group treated with SB-75, but the final tumor volume was significantly suppressed both by D-Trp6-LH-RH and SB-75. In the second experiment, treatment was started 70 days after tumor transplantation and was continued for 6 weeks. Chronic treatment with SB-75 or D-Trp6-LH-RH appeared to completely arrest tumor growth as measured by tumor volume, percentage change in tumor volume, and tumor weight. Serum estradiol was suppressed to undetectable levels and LH levels were also diminished. Histologically, the regressive changes in the treated tumors were due to the enhancement of apoptosis (programmed cell death) of tumor cells. Membrane receptor assays showed that LH-RH binding sites were down-regulated in tumor cells after treatment with SB-75 or D-Trp6-LH-RH. The results indicate that the antagonist SB-75, released from sustained delivery systems, can inhibit the growth of MCF-7 MIII tumors as effectively as the agonist D-Trp6-LH-RH, but more rapidly. In view of its immediate blockade of the pituitary-gonadal axis and the absence of side effects, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of breast cancer.

Present status of agonistic and antagonistic analogs of LH-RH in the treatment of advanced prostate cancer.

The methods for treatment of advanced prostate cancer, based on the agonistic analogs of LH-RH were reviewed. New therapeutic approaches utilizing antagonistic analogs of LH-RH such as SB-75 (Cetrorelix) have been described. Analogs of LH-RH chemically linked to various cytotoxic radicals are also being developed. Combinations of LH-RH agonists or antagonists with superactive somatostatin analogues such as Octastatin (RC-160) or with bombesin/GRP antagonists are being investigated in order to delay or prevent the relapse and improve the therapy for prostate cancer.

Fibrocystic disease of the breast in premenopausal women: histohormonal correlation and response to luteinizing hormone releasing hormone analog treatment.

Sixty-six patients with fibrocystic mastopathy were enrolled in the trial after being selected according to clinical, radioultrasonographic, and histologic criteria. No characteristic hormonal profile was noted in most patients (52%). Estrogen receptors or progesterone receptors, or both, were found in 57% of patients. Hormone receptor levels were correlated with atypical proliferative mastopathy (87.5%). Mastopathy was associated with a uterine fibroma or a fibromatous uterus in 73% of cases. All patients received intramuscular injections of a sustained delivery system (microcapsules) of luteinizing hormone releasing hormone agonist [D-Trp6]-LHRH, Ipsen-Biotech, Paris) for 3 to 6 months. In case of partial response at 3 months, an antiestrogen (tamoxifen, 40 mg/day, for estrogen receptor-predominant lesions) or a progestin (cyproterone acetate, 50 mg/day, for progesterone receptor-predominant lesions) was added to the luteinizing hormone releasing hormone agonist. A complete response was observed in more than half of the patients (n = 35, 53%) treated by [D-Trp6]-LHRH alone (n = 29) or associated with tamoxifen (n = 4) or cyproterone acetate (n = 2). A significant partial response was observed in 30 other patients (45%). Additionally, half of them received inhibitory drugs. The best responses were seen with cyst reformation (complete response, 100%) and fibrous block. Clinical responses to treatment with [D-Trp6]-LHRH alone were independent of hormone receptor status, but synergistic effects occurred with concomitant use of the corresponding inhibitory drugs. We conclude that chronic mastopathy, particularly when associated with uterine fibroma, can be successfully treated by luteinizing hormone releasing hormone analogs in premenopausal women.