Regulatory effect and mechanism of gastrin and its antagonists on colorectal carcinoma

摘要

AIM To explore the effect and mechanism ofgastrin and its antagonists proglumide and somatostatin on coIorectal carcinoma and their clinical significance.METHODS A model of transplanted human colonic carcinoma was established from SW480cell line in gymnomouse body. The volume andweight of transplanted carcinoma was observedunder the effect of pentagatrin (PG), proglumide (PGL) and octapeptide somotostatin (SMS201-995, SMS). The cAMP content ot carcinoma cell was determined by redioimmunoassay and the DNA, protein content and cell cycle were determined by flow-cytometry. The amount of viabIe cells was determined by MTT colorimetric analysis, lP3 content was determined by radioimmunoassay, Ca2+ concentration in cell by fluorometry and PKC activity by isotopic enzymolysis. The expression of gastrin, c-myc,C-fos and rasP21 in 48 cases of colorectal carcinoma tissue was detected by the immunocytochemistry SP method. Argyrophilianucleolar organizer regions was determined withargyrophilia stain.RESULTS The volume, weight, cAMP, DNAand protein content in carcinoma cell, cellamount and proliferation index of S and G2Mphase in PG group were all significantly higher than those of control group. When PG was at theconcentration of 25 mg/ L, the amount of viablecells, lP3 content and Ca2+ concentration in celland membrane PKC activity in PG group weresigniticantly higher than those in control group;when PGL was at a concentration ot 32 mg/L,they dropped to the lowest level in PG (25 mg/L)+ PGL group, but without significant differencefrom the control group. The positive expression rate of gastrin, c-myc, c-fos and rasp21 in carcinoma tissue was 39 .6%, 54 .2%, 47. 9% and54 .2% resPectively and significantly higher than that in mucosa 3 cm and 6 cm adjacent tocarcinoma tissue and normal colorectal mucosa.The positive expression rate of gastrin of highlydifferentiated adenocarcinoma group was significantly higher than that of poorly differentiated and mucinous adenocarcinoma groups. The AgNORs count of carcinoma tissue was significantly higher than that in mucosa 3 cm and 6 cm adjacent to carcinoma tissue and normal colorectal mucosa; and the positive expression of c-myc and c-fos and the AgNORs count in gastrin-positive group was significantly higher than those in gastrin-negative group.CONCLUSION Pentagastrin has a promoting effect on the growth of transplanted human colonic carcinoma from SW480 cell line. PGL hasno obvious effect on the growth of human colonic carcinoma SW480 cell line, but couldinhibit the growth-promoting effect of PG on transplanted carcinoma. Somatostatin can not only inhibit the growth of transplanted human colonic carcinoma from SW480 cell line directlybut also depress the growth-promoting effect ofgastrin on the transplanted carcinoma. Somecolorectal carcinoma cells can produce and secrete gastrin through autocrine, highly-differentiated adenocarcinoma express the highest level gastrin. Endogenous gastrin can stimulate the cell division and proliferation of carcinoma cell and promote the growth of colorectal carcinoma regulating the expression of oncogene omyc, c-fos. Our study has provided experimental basis for the adjuvant treatment using gastrin antagonist such as PGL,somatostatin of patients with colorectalcarcinoma.