Bela Szende

Inhibitory effects of analogs of luteinizing hormone-releasing hormone and somatostatin on pancreatic cancers in hamsters events that accompany tumor regression

Syrian golden hamsters bearing N‐nitrosobis(2‐oxopropyl)amine (BOP)‐induced pancreatic carcinomas were treated for 2 months with the delayed delivery systems of the agonist D‐Trp‐6‐LH‐RH (microcapsules releasing 25 μg/day for 30 days), the somatostatin analog RC‐160 (the microcapsules liberating 48.2 μg/day for 30 days), or with the combination of these two analogues. The increase in the dose of RC‐160 was possible in view of the lack of toxicity of this analog. This higher dose of RC‐160 exerted a greater suppressive effect on pancreatic cancers than the regimens previously used (5‐25 μg/day). RC‐160, D‐Trp‐6‐LH‐RH, and their combination reduced the number of pancreatic carcinomas and significantly inhibited tumor growth as compared with the controls. The combination had the strongest tumor‐inhibitory effect and reduced tumor weight by 85% as compared with controls. Both the light and electron microscopic analysis of the tumors showed that the inhibitory effect was due to the enhancement of apoptosis (programmed cell death) of tumor cells. Insulin‐like growth factor (IGF‐I) receptors were detected immunohistochemically in the untreated tumors and their number decreased after the treatment with the analogues. Binding of D‐Trp‐6‐LH‐RH and RC‐160 to tumor cells was shown immunohistochemically and receptors to these analogues and IGF‐I were also determined biochemically by radioligand titration. Treatment with D‐Trp‐6‐LH‐RH and RC‐160 decreased the binding capacity of receptors for D‐Trp‐6‐LH‐RH and IGF‐I, producing down‐regulation of these receptors. This suggests that pancreatic tumor cells with receptors to these peptides are sensitive to the treatment. This work reinforces the view that the combination of high doses of somatostatin analog RC‐160 with LH‐RH agonists or antagonists should be considered for the development of a new hormonal therapy for ductal pancreatic cancers.

Receptors for D-Trp6-luteinizing hormone-releasing hormone, somatostatin, and insulin-like growth factor I in MXT mouse mammary carcinoma.

Abstract Membrane receptors for d-Trp6-luteinizing hormone-releasing hormone (d-Trp6-LH-RH), somatostatin-14 (SS-14), and insulin-like growth factor I (IGF-I) were estimated in MXT mammary cancers of mice using sensitive multipoint micromethods. The receptors were characterized in untreated animals and following in vivo treatment with microcapsules of the agonist d-Trp6-LH-RH and the somatostatin analog RC-160, which strongly inhibited tumor growth. In the control group, d-Trp6-LH-RH was bound to the single class of saturable, specific, noncooperative receptor sites (Kd , = 29.3 ± 8.48 × 10-9 M; Bmax = 4.55 ± 0.31 pmol/mg membrane protein). Treatment with d-Trp6-LH-RH alone or in combination with RC-160 produced down-regulation of membrane receptors for d-Trp6-LH-RH on MXT mammary tumor cells. RC-160 alone and ovariectomy were without effect on d-Trp6-LH-RH receptors. On the membrane surface of MXT mammary cells, we found one class of high affinity, specific, saturable binding sites for SS-14 (Kd = 4.4 ± 1.9 × 10-9 M; Bmax = 0.58 ± 0.21 pmol/mg membrane protein). Treatment with RC-160 alone or combined with d-Trp6-LH-RH significantly increased both the dissociation binding constant (K d = 18.6 ± 3.5 × 10-9 and 10.1 ± 0.7 × 10-9 M, respectively) and the binding capacity (Bmax = 13.98 ± 1.7 and 21.00 ± 4.0 pmol/mg membrane protein, respectively). We also found specific binding sites (K d = 3.01 ± 0.15 × 10-9 M; Bmax = 2.24 ± 0.96 pmol/mg membrane protein) for IGF-I in the membrane fractions of MXT mammary cancers. Chronic treatment with d-Trp6-LH-RH and RC-160 alone or in combination, as well as ovariectomy, significantly decreased the dissociation binding constant of IGF-I membrane receptors on MXT mammary cells. Our results strongly suggest an important role of LH-RH, SS-14, and IGF-I in the growth of MXT mammary carcinoma. Changes in characteristics of receptors after treatment with analogs of LH-RH and SS-14 along with tumor growth inhibition provide additional support for the direct effect of these peptides on tumor cells. A possible significance of these findings as applied to a clinical environment is discussed.