Programmed cell death (apoptosis) in pancreatic cancers of hamsters after treatment with analogs of both luteinizing hormone-releasing hormone and somatostatin.

Abstract

Female Syrian golden hamsters with Nnitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic cancers were treated with long-acting microcapsular preparations of the 6-D-tryptophan analog of luteinizing hormone-releasing hormone LH-RH), releasing 25 ,ug/ day; the somatostatin analog D-Phe-C'ys-Tyr-D-Trp-Lys-ValUs-Trp-NH2 , liberating 15 ,ug/day; and the combination of these two peptides. Therapy with analogs was initiated 24 weeks after initial administration of BOP. These treatments resulted in significantly better survival of all animals as compared to BOP controls; body weights of surviving peptide-treated animals were significantly higher than those of the BOP controls. All 15 BOP-control animals had pancreatic cancers. In the group treated with RC-160 four hamsters were free of tumors, whereas therapy with [D-Trp6]LH-RH resulted in seven tumor-free animals, and combination of RC-160 and [D-Trp6]LH-RH resulted in eight tumor-free animals from groups of 15. Only preblastomatous lesions were found in these animals. Average tumor weight of animals in all peptidetreated groups, sacrificed 60 days after beginning the peptide treatment, was significantly lower than that of BOP controls. No significant differences were seen between the various peptide-treated groups. Histologically, analog-treated tumors of hamsters showed striking regressive changes characteristic of programmed cell death (apoptosis). This apoptosis presumably resulted from hormonal effects on tumor cells from prolonged treatment with these analogs of hypothalamic hormones. Our present data confirm the beneficial effect of long-acting microcapsules of LH-RH and RC-160 on pancreatic carcinoma and suggest a mode of action for these peptides. The feasibility ofapplying this treatment with analogs of hypothalamic.hormones to human pancreatic carcinoma can be envisioned from these studies.Carcinoma of the pancreas causes over 20,000 deaths per year in the United States (1). Patients with this tumor have a poor prognosis; the 5-yr survival rate is very low (2, 3). Resectability is only -15%, and radiotherapy and chemotherapy are usually ineffective (4). Recent experimental and clinical findings indicate that pancreatic cancer may be sensitive to sex steroids (5-9).Studies in experimental models of pancreatic cancer (10-16) and preliminary clinical trials (17) (18). These findings suggest that some antiproliferative effects of LH-RH analogs in pancreatic cancer could also be mediated directly through specific membrane receptors located on the tumor cells.Somatostatin and its analogs can effectively suppress the release and/or action of gastrointestinal hormones and interfere with the effects of growth factors (19)(20)(21)(22)(23)(24). These mechanisms of action of somatostatin analogs can be used to inhibit the growth of pancreatic cancers.In our previous studies we reported the use of LH-RH agonists and somatostatin analogs for the treatment of experimental pancreatic cancer in rats and hamsters (13)(14)(15)25). We also showed that combinatio...

The effects of gonadotrophin releasing hormone analogues in prostate cancer are mediated through specific tumour receptors

“…There have also been reports of the presence of GnRH-binding sites in breast cancer cells (Eidne et al, 1987), pancreatic tumours (Szende et al, 1989) and induced rat prostatic cancers (Kadar et al, 1988). The binding of GnRH to breast cancer cells has been shown to result in growth modulation (Millar et al, 1985;Eidne et al, 1987).…”

Drug-target interactions: only the first step in the commitment to a programmed cell death?

“…Apoptotic cells express new surface signal molecules and they are rapidly recognised by phagocytes and engulfed so that the cell dies without inflicting damage to viable neighbours Duvall et al, 1985;Savill et al, 1990). Apoptosis occurs spontaneously in solid tumours of various types (Wyllie, 1985;Searle et al, 1975;Szende et al, 1989;Sarraf & Bowen, 1988;Kyprianou et al, 1990;Kerr & Searle, 1981;Kerr & Lamb, 1984 is dictated by the balance between cell gain (proliferation) and cell loss (cell death and differentiation) (Steel, 1985). Cell loss is sometimes considerable and apoptotic cell death is a key player in the equation which predicts tumour size and development.…”

A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity.

“…This analog had practically no growth hormone (GH) release inhibitory activity either in superfused rat pituitary cells or in rats in vivo. TT-232 showed a strong antiproliferative effect both in vitro and in vivo (14)(15)(16) and induced apoptosis in a pancreatic tumor cell line (17) as demonstrated for other somatostatin analogs (18,19).…”