Systematic Reviews
Copyright ©The Author(s) 2021.
World J Gastroenterol. Nov 28, 2021; 27(44): 7716-7733
Published online Nov 28, 2021. doi: 10.3748/wjg.v27.i44.7716
Table 1 Summary of basic research studies (animal models)
AuthorAim of studyPPI investigatedSpecies strain, genderMethods of CRC inductionPPI treatmentExperimental/ control groupOutcome measureMain findingsMechanism studiedRole of PPI in CRC
Graffner et al[16] 1992To determine the influence of PPI-induced endogenous hypergastrinemia on growth in CRC-implanted miceOMEBALB/C mice, MMC-26 tumor cells injected SC in epigastric regionDaily for 19 d, 400 μmol/kg, PO18/18Tumor size, survival5-fold higher serum gastrin levels in OME-treated animals than controls. No differences in tumor size, tumor weight, survival and metastatic potential (61% vs 72%, P = NR) between tumor-bearing treated and control groupTrophic effect of gastrinNE
Penman et al[20] 1993To assess the influence of OME-induced hypergastrinemia on CRC development in animal modelsOMESprague-Dawley rats, F12 (weekly) SC azoxymethane (10 mg/kg/wk)Daily for 27 wk, 40 μmol /kg, PO19/20Number of tumors, position, volume; metastatic disease9-10-fold higher gastrin levels in OME-treated groups than control groups. Significantly fewer OME-treated rats developed tumors compared to control group (63% vs 95%, P < 0.02). Number of tumors were also significantly lower in OME-treated rats. Average tumor size and invasiveness of CRC was similar for both groupsTrophic effect of gastrinPE
Hurwitz et al[18] 1995To evaluate effect of omeprazole-induced hypergastrinemia on carcinogen-induced CRC in ratsOMESprague-Dawley rats, MSix (weekly) IP methylazoxymethanol (30 mg/kg) Daily for 10 wk, 40 mg/kg, gastric gavageNRNumber of tumors, volume and total tumor burden, biochemical and histological analysisSerum gastrin levels were elevated 6-fold in OME-treated animals vs controls. No differences in tumor number, tumor volume, and total tumor burden between treated and control group. No histological (crypt/mucosal height) or biochemical features in CRC-free regions of colonTrophic effect of gastrinNE
Pinson et al[17] 1995To assess if hypergastrinemia enhances progression or invasiveness of CRCOMESprague-Dawley rats, MSix (weekly) IP methylazoxymethanol (30 mg/kg) Daily for 10 wk, 14 or 40 mg/kg, gastric gavage162/108Number of tumors, volume and total tumor burden, histological analysisPlasma gastrin levels in the treated groups (low-dose OME, high-dose OME, ranitidine) were 3–5-fold higher than controls. Crypt height/mucosal height ratio of CRC-free colonic mucosa was similar between all groups. No significant differences in tumor number, tumor burden and invasiveness between OME-treated and control groups. Trophic effect of gastrinNE
Chen et al[19] 1998To examine trophic effects of endogenous hypergastrinemia colonic mucosa and transplanted colon adenocarcinoma in ratsOMESprague-Dawley rats, MInjection of K-12 cell line (Established in syngeneic BDIX rats via induction using 1,2-dimethylhydrazine)Daily for 10 d, 400 μmol/kg, PONRTumor weight and volume, histological analysis, labelling indexOME treatment and fundectomy raised serum gastrin levels by 4-5-fold. OME-treatment did not stimulate growth of transplanted tumor (K-12) cells, while fundectomy suppressed CRC growth (decreased labelling index, weight and volume of tumor) Sustained hypergastrinemia did not affect the thickness and labelling index of normal colon mucosaTrophic effect of gastrinNE
Kim et al[23] 2010To evaluate chemo-preventive properties of omeprazole in a colitis-associated CRC mouse model OMEC57BL/6 mice, FColitis induction - 15 cycles of 0.7% DSS in drinking waterNR, 10 mg/kg, IP12/24Tumor burden, biochemical and histological analysisOME-treated group developed significantly lower number of colon tumors than control groups. OME administration also resulted in decreased inflammatory markers (TNF-α, serum NO, and colon TBA-RS levels), attenuated expression of MMP, COX-2, NO synthase, and β-catenin, and greater apoptotic indexCytostatic propertiesPE
Patlolla et al[22] 2012To assess chemo-preventive effects of omeprazoleOMEF344 rats, MTwo (weekly) SC azoxymethane (15 mg/kg)9 wk, 200/400 ppm, PO30/18Aberrant crypt foci incidenceOmeprazole inhibited the AOM-induced colonic foci formation in a dose-dependent mannerCytostatic propertiesPE
Han et al[24] 2014To study the effects of PPI on colitis-associated carcinogenesisPANAPCMin/+ mice, MGenetically engineered mutation in APC geneThrice weekly for 10 wk, 8 mg/kg, IPNR/8Number and size of intestinal polypsGastrin + PPI exerted significant anti-polyposis effect through β-catenin inactivation, increased apoptosis, anti-angiogenic, and MAPK inactivation relevant to decreased levels of pro-inflammatory mediatorsCytostatic propertiesPE
Zeng et al[26] 2016To evaluate the effect of pantoprazole as TOPK inhibitor in vivo and in vitro PANNon-obese diabetic-SCID miceHCT 116 cells inoculated SC into left flankEvery 2 d for 19 d, 100 mg/kg, IP 8/8Tumor volume, immunohistochemical analysisTumors treated with PAN grew significantly more slowly, and the size of tumors was smaller compared with the control group. PAN-treated group had lower average tumor volume per mouse compared to controls (111 mm3 vs 285 mm3, P < 0.05). Average body weight was similar throughout the study indicating no toxic effects of PAN in the mice IMHC for phosphorylated histone H3 revealed substantially decreased expression in PAN-treated group compared to controlTOPK inhibitionPE
Zheng et al[27] 2017To evaluate the effect of PPI as a TOPK inhibitor in vivo and in vitro ILACB-17/Icr-scid miceHCT 116 cells inoculated SC into left flankDaily for 19 d, 150 mg/kg, PO8/8Tumor volume, immunohistochemical analysisEstimated tumor volumes of treatment groups were less than that of the control group. No toxicity or differences in body weight were observed. Expression levels of phosphorylated histone H3 were substantially decreased in ilaprazole-treated groups compared with the control groupTOPK inhibitionPE
Wang et al[25] 2017To investigate the chemosensitizing potential of PPI in CRCPANBALB/C mine, FHT29 cells injected SCWeekly for 4 wk, 30 mg/kg, IPNRTumor burdenPAN combined with 5-FU demonstrated greater inhibition of tumor growth and smaller tumor sizes compared to 5-FU aloneChemosensitizing propertiesPE