Ana Maria Comaru-Schally

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.

NEW HYPOTHALAMIC HORMONE, CORTICOTROPIN-RELEASING FACTOR, SPECIFICALLY STIMULATES THE RELEASE OF ADRENOCORTICOTROPIC HORMONE AND CORTISOL IN MAN

Abstract A synthetic preparation of the 41-aminoacid-residue peptide recently isolated from ovine hypothalami and characterised corticotropin-releasing factor (CRF), has been given intravenously to six normal men. 100 μg synthetic CRF caused rises in circulating levels of adrenocorticotropic hormone (ACTH) and cortisol but had no effect on levels of prolactin, growth hormone, thyrotropin, or gonadotropins. Its specific action suggests that it, or a related peptide, may be a CRF in man, and it may provide the basis for a new clinical test of pituitary ACTH reserve.

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. Prostate 45:158–166, 2000.

Antitumor Effects of Analogs of Hypothalamic Hormones in Endocrine-Dependent Cancers

Summary A new approach to the treatment of endocrine-dependent tumors based on analogs of hypothalamic hormones is in the early stages of development, but appears promising and significant. Administration of hypothalamic hormones can mimic hypophysectomy and gonadectomy, and is essentially devoid of side effects. A successful use of agonistic analogs of LH-RH for treatment of endocrine-dependent prostate cancer has been documented in several hundred patients. Experimental studies suggest that agonists and/or antagonists of LH-RH might be useful for treatment of breast cancer and pituitary tumors. Our work in animal models also indicates that analogs of somatostatin, alone or combined with LH-RH agonists, could be considered for therapy of chondrosarcomas, osteosarcomas, and pancreatic cancer. Experiments are in progress on the use of LH-RH analogs for treatment of ovarian cancer, neoplasms of the female genital tract, and for protection against gonadal damage during chemotherapy. These investigations should extend the concepts of endocrine treatment of cancers.

Membrane receptors for peptides in experimental and human pancreatic cancers

Membrane receptors for [D-Trp6]-luteinizing hormone-releasing hormone ([D-Trp6-LH-RH), somatostatin (SS-14), and epidermal growth factor (EGF) were investigated in experimental N-nitrosobis-(2-oxopropyl)-amine (BOP)-induced pancreatic cancers of hamsters and in specimens of normal human pancreas and human pancreatic cancer obtained from autopsies. Membrane receptors for [D-Trp6]-LH-RH were absent in the pancreas of normal hamsters, but appeared after the carcinoma was induced with BOP. Binding capacity of SS-14 receptors was lower in membranes of BOP-induced pancreatic cancers than in the normal pancreas. In the BOP-induced pancreatic cancers, the receptors were also characterized following in vivo treatment of hamsters with microcapsules of the agonist [D-Trp6]-LH-RH, somatostatin analog RC-160, and the combination of both peptides, which resulted in significant tumor inhibition. Therapy with [D-Trp6-LH-RH and RC-160, alone or in combination, decreased the binding capacity of receptors for [D-Trp6-LH-RH, but increased Bmax for SS-14. There were no significant changes in characteristics of the EGF receptor following these therapies. Membranes from human pancreatic cancers showed binding sites for [D-Trp6]-LH-RH, but no binding was detected in normal human pancreas. The presence of receptors for LH-RH in pancreatic tumors of hamster and humans raises the intriguing possibility that LH-RH could be involved in complex interactions that contribute to the appearance of pancreatic cancer. The binding capacity of receptors for SS-14 in human pancreatic cancer membranes was lower, while Bmax for EGF2 was higher, as compared to normal pancreas. Observed changes in receptors and tumor suppression suggest that the agonist [D-Trp6-LH-RH and somatostatin analogs might exert some direct inhibitory effects on experimental pancreatic cancer of hamsters. It is possible that LH-RH agonists and somatostatin analogs could also be used for treatment of human pancreatic cancer. The presence of membrane receptors for [D-Trp6]-LH-RH, SS-14, and EGF in specimens of human pancreatic cancer also implies that this malignancy might be responsive to hormonal manipulations.

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.

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.

Treatment of leiomyomata uteri with D-Trp6-luteinizing hormone-releasing hormone

Suppression of the secretion of gonadal steroids by chronic administration of a superactive agonist of luteinizing hormone-releasing hormone (LH-RH) was used for treatment of leiomyomata uteri. Ten menstruating women, presenting with a total of 20 uterine leiomyomas, were treated for 3 months with daily subcutaneous injections of D-Trp6-LH-RH. Serum estradiol (E2) levels were suppressed rapidly in five patients and were decreased in other patients. At the end of therapy, leiomyomas regressed completely in three patients, while five patients showed a decrease of more than 40% in the volume of leiomyomas. The reduction in tumor size was correlated with the rapidity of the fall in serum E2 levels. In one patient, the leiomyomata increased in size during treatment, and one woman had a poor clinical response. The agonist was well tolerated and few side effects were observed. Therapy with LH-RH agonists offers an alternative in the management of some uterine leiomyomas.

Antitumor effects of analogs of LH-RH and somatostatin: Experimental and clinical studies

Many clinical approaches for the treatment of hormone-sensitive tumors are being developed based on analogs of LH-RH and somatostatin. Inhibition of the pituitary-gonadal axis forms the basis for oncological applications of LH-RH agonists like [D-Trp6]-LH-RH and new LH-RH antagonists free of edematogenic effects such as [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit6,D-Ala10]-LH -RH (SB-75). Agonists and antagonists of LH-RH have been used in patients with prostate cancer and might be also beneficial for the treatment of breast cancer and ovarian, endometrial and pancreatic carcinomas. Some of the effects of LH-RH analogs can be due to direct action since LH-RH receptors have been found in these cancers. The use of sustained delivery systems based on microcapsules of PLG, makes the treatment more efficacious. Octapeptide analogs of somatostatin such as D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and related analogs were designed specifically for antitumor activity. These somatostatin analogs, by virtue of having a wide spectrum of activities appear to inhibit various tumors through multiple mechanisms. Direct antiproliferative actions of somatostatin analogs appear to be mediated by specific receptors located on tumor cells. High affinity binding sites for RC-160 and related analogs have been found in human pancreatic, prostate, breast and ovarian cancers and brain tumors such as meningiomas. In vivo administration of analog RC-160 inhibits the growth of Dunning R-3327 prostate cancers in rats, MXT mammary tumors in mice and BOP-induced ductal pancreatic cancers in hamsters. Combination of microcapsules of RC-160 with [D-Trp6]-LH-RH results in synergistic potentiation of the inhibition of these cancers. Somatostatin analog RC-160 and LH-RH antagonist SB-75 are the object of further experimental studies and clinical trials aimed at the exploration of their inhibitory effects on the processes of malignant growth.

Treatment of endometriosis with a delayed release preparation of the agonist D-Trp6-luteinizing hormone-releasing hormone: long-term follow-up in a series of 50 patients *

Fifty patients with proven endometriosis were treated for 6 to 9 months with a delayed release preparation of microcapsules of the luteinizing hormone-releasing hormone (LH-RH) agonist D-Trp6-LH-RH, injected intramuscularly at monthly intervals. After a transitory ovarian stimulation at the onset of treatment, serum estradiol was suppressed to menopausal levels (50 pg/mL). This state of hypogonadism was reversible after the discontinuation of treatment, and menses resumed within 4 months after the last injection. Pelvic pain was relieved during treatment in 87.5% of patients. After a follow-up period of up to 37 months, 24 patients are in clinical remission and 9 experienced recurrence of endometriosis 7 to 14 months after completing treatment. One patient failed to respond to therapy with the agonist and 7 patients were lost to follow-up. Among 16 previously infertile patients with no other factors contributing to infertility, 7 became pregnant; 2 of these pregnancies were the result of gamete intrafallopian transfers. An eighth patient without documented infertility also conceived spontaneously. Side effects due to hypoestrogenism were reported by nearly all patients. In conclusion, D-Trp6-LH-RH microcapsules are effective and easily-administered agents for the treatment of endometriosis.