exenatide and Adenocarcinoma

Topics: Adenocarcinoma; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Diabetes Mellitus, Type 2; Disease Management; Drug Resistance; Drug Therapy, Combination; Exenatide; Fluorouracil; Humans; Hyperglycemia; Hyperglycemic Hyperosmolar Nonketotic Coma; Hypoglycemic Agents; Insulin; Leucovorin; Male; Malnutrition; Metformin; Middle Aged; Nausea; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Peptides; Sulfonylurea Compounds; Venoms

Incretin-based therapies have been associated with an increased risk of pancreatitis. Recently, various histological abnormalities have been reported in human pancreatic tissue from brain-dead organ donors who had been exposed to incretin-based drugs. In the present study we examined pancreatic tissue collected at surgery.. Human pancreatic tissue from 7 type 2-diabetic patients treated with incretin-based drugs (type 2-I), 6 diabetic patients without incretin treatment (type 2-NI), 11 patients without diabetes (no diabetes group) and 9 brain-dead organ donors (BDOD group) was examined.. Fractional beta-cell area was reduced in the type 2-NI group compared to the group without diabetes (P < .05), but there was no difference compared to the type 2-I patients. Alpha-cell area (P = .30), beta-cell replication (P = .17) and alpha-cell replication (P = .91) were not different. There were also no differences in acinar cell (P = .13) and duct cell replication (P = .099). Insulin-positive duct cells were more frequent in the type 2-I and the BDOD groups (P = .034). No co-expression of insulin and glucagon was detected. Pancreatic intraepithelial neoplasia (PanIN) lesions were very rare, all low-grade (PanIN 1a and 1b) and tended to occur more frequently in the type 2-I group (P = .084).. The present results did not reveal marked histological abnormalities in the pancreas of incretin-treated patients with type 2 diabetes. Low numbers of specimens available and a large inter-individual variability of the findings warrant caution regarding the interpretation of histological data concerning drug effects on the human pancreas.

Topics: Acinar Cells; Adamantane; Adenocarcinoma; Adult; Aged; Carcinoma in Situ; Case-Control Studies; Cystadenoma; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Dipeptides; Exenatide; Female; Glucagon; Glucagon-Secreting Cells; Humans; Incretins; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Middle Aged; Neuroendocrine Tumors; Nitriles; Organ Size; Pancreas; Pancreas, Exocrine; Pancreatic Neoplasms; Pancreatitis, Chronic; Peptides; Pyrrolidines; Sitagliptin Phosphate; Tissue Donors; Venoms; Vildagliptin

Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells.. Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves.. Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 μg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice.. These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Survival; Colonic Neoplasms; Exenatide; Hyperalgesia; Hypoglycemic Agents; Male; Mice; Mice, Inbred BALB C; Neurites; Organoplatinum Compounds; Oxaliplatin; PC12 Cells; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Venoms