Gastrointestinal Cancer Refractory to Chemotherapy: A Role for Octreotide?

Cascinu, Stefano; Catalano, Vincenzo; Giordani, Paolo; Baldelli, Anna Maria; Agostinelli, Romina; Catalano, Giuseppina

doi:10.1159/000049165

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…The diverse results of the studies found in literature may be caused by methodological alterations and clinical differences [58]. Among the five known somatostatin receptors primarily SSTR2 and SSTR5 mediate the antiproliferative effect of SST and its analogues.…”

Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation-Related Reduced Somatostatin Production Promotes Uncontrolled Cell Proliferation in Colorectal Cancer

et al. 2015

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BackgroundSomatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line.MethodsColonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion.ResultsIn case of normal aging SST mRNA expression did not alter, but decreased in cancer (p<0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70%±0.79%) compared to CRC (0%±0%) (p<0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2%±11.6%) compared to healthy young individuals (3.5%±1.9%) (p<0.05).ConclusionsIn cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation.

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Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation-Related Reduced Somatostatin Production Promotes Uncontrolled Cell Proliferation in Colorectal Cancer

et al. 2015

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“…subcutaneously (s.c.) for 2 months lowered serum IGF-I, caused major side effects such as cramps, but had no effect on tumors [189]. Cascinu et al [190] reviewed these clinical studies and concluded that the results available suggest that octreotide is not effective in the management of untreated patients with advanced GI cancer, but additional studies of octreotide in chemotherapy-resistant patients are needed [190]. Avastin (bevacizumab), a recombinant monoclonal antibody targeting VEGF, is in a phase III clinical trial in patients with advanced colon cancer.…”

Section: Clinical Studiesmentioning

confidence: 99%

“…The overall results indicate that treatment with octreotide and other octapeptide analogs of somatostatin is not effective in patients with advanced pancreatic cancer [192]. Cascinu et al [190] concluded that although the results of clinical trials suggest that octreotide is not effective in untreated patients with advanced pancreatic cancer, additional details are needed to evaluate octreotide in chemotherapy refractory patients in order to clarify its effects not only on the survival, but also on the quality of life of the patients [190].…”

Section: Clinical Trialsmentioning

confidence: 99%

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

Schally

Szepesházi

Nagy

et al. 2004

Cellular and Molecular Life Sciences (CMLS)

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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.

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“…As discussed by Cascinu et al [83] in another paper in this volume, there is an urgent need for large controlled trials to evaluate the efficacy of adjuvant therapies after surgery. Somatostatin analog therapy may, as discussed earlier for colorectal and pancreatic cancer, be a valuable treatment for gastric cancer to potentiate the effects of chemotherapy and via their stimulatory effect on hepatic RES activity inhibit the growth and development of liver metastases.…”

Section: Gastric Cancermentioning

confidence: 99%

Somatostatin Analogs in Oncology: A Look to the Future

Jenkins

Kynaston²,

Davies³

et al. 2001

Chemotherapy

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In the past 15 years considerable advances have been made in our understanding of the molecular pharmacology of the mechanisms whereby somatostatin and its analogs mediate their direct and indirect antineoplastic effects. However, some important issues remain to be resolved, in particular the functional roles of the individual somatostatin receptors (SSTR-1–5) in tumor tissue and up- or downregulation of the hSSTRs with prolonged administration of somatostatin analogs. Answers to these questions are essential before we can maximize the therapeutic efficacy of somatostatin analogs in cancer. For example, is continuous administration more or less effective than intermittent therapy? The role of somatostatin analogs in the management of acromegaly and to a lesser extent neuroendocrine tumors is firmly established. The development of depot preparations of all 3 somatostatin analogs currently available for clinical use will undoubtedly improve both patient compliance and quality of life in patients with these conditions. There are only likely to be minor differences in the therapeutic efficacy of octreotide, lanreotide and vapreotide since all three analogs exert the majority of their antineoplastic effects via hSSTR-2 and hSSTR-5 and at the end of the day, price may well dictate which of these drugs oncologists use to provide symptomatic palliation of acromegaly and neuroendocrine tumors. Apart from some notable exceptions, somatostatin analog therapy has proven to be very disappointing in the management of advanced malignancy. Improvements in the management of solid tumors are likely to come only from combination therapy of somatostatin analogs with cytotoxic agents or other hormones in both advanced malignancy and in the adjuvant setting. Clinical trials with clear-cut objective outcome measures and health-related quality of life assessment are needed to evaluate the therapeutic efficacy of combination treatment in advanced malignancy and as an adjuvant to surgery. Particular attention needs to be paid to possible adverse effects of somatostatin analog therapy on the immune response to cancer. Further studies are required to establish whether the adverse effects of somatostatin analog therapy alone or in combination with cytotoxics or other hormones can be reversed with appropriate immunomodulatory treatment. Targeted somatostatin analog radiotherapy and chemotherapy are currently being investigated and the results of these studies are awaited with interest. Novel approaches using combinations of somatostatin analogs with antiangiogenic drugs or gene therapy are of particular interest and may provide important advances in the management of cancer in the not too distant future.

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Gastrointestinal Cancer Refractory to Chemotherapy: A Role for Octreotide?

Cited by 9 publications

References 29 publications

Promoter Hypermethylation-Related Reduced Somatostatin Production Promotes Uncontrolled Cell Proliferation in Colorectal Cancer

Promoter Hypermethylation-Related Reduced Somatostatin Production Promotes Uncontrolled Cell Proliferation in Colorectal Cancer

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

Somatostatin Analogs in Oncology: A Look to the Future

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