Endocrine, Gastrointestinal, and Antitumor Activity of Somatostatin Analogues

Cai, Renzhi; Torres‐Alemán, Ignacio; Redding, Tommie W.; Szőke, Balázs; Fu, Daotian; Hierowski, Marion T.; Colaluca, J.; Konturek, Stanisław J.

doi:10.1007/978-1-4684-5152-8_7

Cited by 30 publications

(57 citation statements)

References 44 publications

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“…The present formulation of the microcapsules, which can be conveniently injected at monthly intervals, should have a higher efficacy than discontinuous administration and would ensure patient compliance. This use of microcapsules might allow the establishment of continuous therapeutic levels of RC-160 and permit new approaches in the management of pancreatic cancer and other malignancies and conditions (6,18,19). Microcapsules of RC-160 could also be tried in combination with LH-RH agonists for the treatment of breast and prostate cancer (5,6,18).…”

Section: Methodsmentioning

confidence: 99%

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Radioimmunoassay for octapeptide analogs of somatostatin: measurement of serum levels after administration of long-acting microcapsule formulations.

Mason-Garcia

Vaccarella

Horváth

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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The development of a long-acting delivery system for D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), an octapeptide analog of somatostatin, required the establishment of a method for determining the concentration of this analog in serum during treatment. A sensitive and specific radioimmunoassay (RIA) for RC-160 was developed and used for following the rate of liberation of this peptide from microcapsules of poly(DL-lactide-coglycolide). Antibodies were generated in a rabbit against RC-160 coinugated to bovine serum albumin with glutaraldehyde. At an antiserum dilution of 1:100,000, the antibodies bound approximately 25% of added radiolabeled RC-160. Somatostatin octapeptide analogs that had a disulfide bridge showed crossreactivity with the antiserum, but analogs without the disulfide bridge and other peptides tested did not crossreact. The minimum detectable dose of RC-160 was 10 pg. Intra-and interassay coefficients of variation ranged from 9.1% to 12.8% and from 14% to 30%, respectively. The RIA was suitable for direct determination of RC-160 in serum. Eleven prototype batches of microcapsules were tested in rats, and the rate of release of the analog from the microcapsules was followed. An improved batch of microcapsules made from RC-160 pamoate maintained high serum levels of RC-160 for more than 30 days after intramuscular injection. The RIA should be of value for monitoring levels of this analog in serum during long-term therapy.Superactive analogs of somatostatin such as D-Phe-CTs-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cs-TyTrLys-Val-C's-Thr-NH2 (RC-121) show a high potency and a long duration of action in tests for inhibition of growth hormone release and much lower activity for suppression of insulin, glucagon, and gastric acid secretion (1, 2). This indicates a marked selectivity in their biological actions, which could make them useful for the treatment of endocrinerelated diseases such as type I diabetes mellitus and diabetic retinopathy.There is also experimental evidence that somatostatin analogs might be used to treat pancreatic cancer (3) by inhibiting the release of gastrointestinal hormones such as secretin, gastrin, and cholecystokinin or by stimulating the dephosphorylation of membrane receptors for the epidermal growth factor (4). In addition, somatostatin analogs of this class inhibit the growth of experimental prostate and mammary tumors by suppressing the levels of prolactin, growth hormone, and insulin-like growth factor I (IGF-I, somatomedin C) (5) and could be used as adjuncts to therapy with analogs of luteinizing hormone-releasing hormone (LH-RH).Thus, therapeutic application of these analogs in the treatment of various hormone-sensitive tumors is likely (6).The use of RC-160 and related analogs for the therapy of hormone-dependent tumors and endocrine disorders would be greatly enhanced by delayed delivery systems capable of maintaining controlled levels of the peptide over an extended period of time. Consequently, we started the development of such a long-acti...

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Section: Methodsmentioning

confidence: 99%

“…Thus, therapeutic application of these analogs in the treatment of various hormone-sensitive tumors is likely (6).…”

mentioning

confidence: 99%

Radioimmunoassay for octapeptide analogs of somatostatin: measurement of serum levels after administration of long-acting microcapsule formulations.

Mason-Garcia

Vaccarella

Horváth

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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“…Negative growth-regulatory properties of somatostatin have been shown in a number of human tumours, including breast cancer (Schally, 1988), suggesting that it may have therapeutic potential in oncology. The clinical use of native somatostatin, however, is limited by its short half-life in the circulation and the broad spectrum of its physiological actions.…”

mentioning

confidence: 99%

“…The clinical use of native somatostatin, however, is limited by its short half-life in the circulation and the broad spectrum of its physiological actions. These problems have been circumvented by the development of synthetic structural analogues of somatostatin with enhanced selectivity and greater stability (Schally, 1988;Schally et al, 1986). Growth inhibition by somatostatin and its analogues occurs both indirectly, through the modulation of secretion of trophic peptide hormones and growth factors, and directly via interaction with tumour cells.…”

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confidence: 99%

Analysis of somatostatin receptor subtype mRNA expression in human breast cancer

Evans

Crook²,

Laws³

et al. 1997

Br J Cancer

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Summary Somatostatin is a widely distributed inhibitory peptide with growth-inhibitory effects in several human tumours, including breast cancer, raising the possibility that it may have therapeutic potential. The effects of somatostatin are mediated via a family of cell-surface receptors that differ in their tissue distribution, pharmacological properties and intracellular response mediators, suggesting that they mediate different functions of the peptide. We have analysed the expression of somatostatin receptor subtype (SSTR1-5) mRNA in normal and malignant breast tissue. Receptor expression was analysed by reverse transcription-polymerase chain reaction (RT-PCR) using receptor subtype-specific primers and by in situ hybridization (ISH) with riboprobes synthesized by in vitro transcription of cloned PCR products. A total of 51 breast carcinomas, 36 samples of matched normal tissue, two axillary node metastases and eight normal/benign breast tissue samples were analysed. SSTR2 expression was ubiquitous in both normal and malignant breast tissue. Expression of SSTR5 was detected in approximately one-third of tumour and normal tissue, but fewer than 13% of all tissues expressed SSTR1, 3 and 4. These data suggest that SSTR2 gene expression is ubiquitous in breast cancer. Although this is unlikely to have diagnostic or prognostic significance, SSTR2-specific somatostatin analogues may have therapeutic potential in breast cancer.

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“…Somatostatin inhibits the pancreatic exocrine secretion of protein and bicarbonate (Boden et al, 1975) and the endocrine secretion of cholecystokinin, gastrin and secretin (Schally et al, 1978). These hormones have been shown to have trophic effects on the growth of normal pancreas and also on pancreatic tumours (Johnson, 1981;Schally et al, 1986). It has therefore been proposed that somatostatin may be capable of inhibiting pancreatic tumour growth indirectly via the suppression of secretion of pancreatic trophic hormones and/or by direct effects on the tumour itself Liebow et al, 1989).…”

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confidence: 99%

Human pancreatic cancer cell lines do not express receptors for somatostatin

Gillespie

Poston²,

Schächter³

et al. 1992

Br J Cancer

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Summary The in vivo administration of somatostatin (SS) or its analogues is capable of suppressing the growth of pancreatic cancer in experimental animals. We examined the effects of SS-14 and its analogue RC-160 on the in vitro growth of two human pancreatic cancer cell lines MiaPaCa-2 and Panc-1 stimulated with epidermal growth factor (EGF) or insulin-like growth factor 1 (IGF-1). Neither SS-14 nor RC-160 inhibited the growth of either cell line. In contrast RC-160 did inhibit the EGF-stimulated growth of a rat pancreatic cancer cell line AR42J. Binding studies with '251-Tyr" somatostatin revealed the presence of a single class of high affinity binding sites with a Kd of 0.20 ± 0.05 nM and a B.,,, of 2.1 + 0.26 pmoles mg-' protein on AR42J but no displaceable binding was observed on MiaPaCa-2 or Panc-1. We conclude that lack of receptors accounts for the failure of SS-14 and RC-160 to influence the growth of human pancreatic cancer in vitro. These results, taken together with other findings, lead us to question the therapeutic efficacy of somatostatin and its analogues as mono-therapy in the treatment of human pancreatic cancer.

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Endocrine, Gastrointestinal, and Antitumor Activity of Somatostatin Analogues

Cited by 30 publications

References 44 publications

Radioimmunoassay for octapeptide analogs of somatostatin: measurement of serum levels after administration of long-acting microcapsule formulations.

Radioimmunoassay for octapeptide analogs of somatostatin: measurement of serum levels after administration of long-acting microcapsule formulations.

Analysis of somatostatin receptor subtype mRNA expression in human breast cancer

Human pancreatic cancer cell lines do not express receptors for somatostatin

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