pituitrin and Colorectal-Neoplasms

Alcohol intake is a well-known lifestyle risk factor for CRC, and an increasing number of studies have revealed that alcohol intake is also tightly associated with CRC metastasis. However, the effect of alcohol on CRC metastasis and its underlying mechanism remain unclear.. A retrospective cohort study was performed to investigate the characteristics of patients with alcohol-related CRC. The effects of ethanol on the biological behaviours of CRC cells were assessed through in vivo and in vitro assays using the Lieber-DeCarli ethanol liquid diet and ethanol, respectively. The ethanol-mediated signalling pathway and downstream factors were screened through ELISA, western blot, immunofluorescence and co-immunoprecipitation.. Most patients with alcohol-related CRC, particularly those with tumour metastasis, were characterized by a notably higher circulating ethanol level and a lower systemic acetaldehyde level. Moreover, CRC cells accumulated in ethanol, but not acetaldehyde, to notably higher levels compared with adjacent normal cells. Alcohol intake significantly promoted CRC metastasis via the ethanol-mediated TGF-β/Smad/Snail axis, and ethanol induced the cytoplasmic mislocalization of RUNX3 and further promoted the aggressiveness of CRC by targeting Snail. Pirfenidone (PFD) significantly eliminated the effects of ethanol on CRC metastasis by specifically blocking TGF-β signalling.. Alcohol intake plays a vital role in CRC metastasis via the ethanol-mediated TGF-β/RUNX3/Snail axis, and PFD might be a novel therapeutic management strategy for CRC.

Topics: Alcohol Drinking; Animals; Biomarkers; Cell Line, Tumor; Colorectal Neoplasms; Core Binding Factor Alpha 3 Subunit; Disease Models, Animal; Epithelial-Mesenchymal Transition; Humans; Incidence; Mice; Neoplasm Metastasis; Neurophysins; Protein Binding; Protein Precursors; Protein Transport; Signal Transduction; Snail Family Transcription Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vasopressins; Xenograft Model Antitumor Assays

Poor drug uptake secondary to the hypovascularity of colorectal liver metastases may partially explain their limited response to hepatic artery chemotherapy. Vasoconstrictors can increase tumor perfusion but their effect on drug uptake has not been well-characterized. The aim of this study was to determine whether vasopressin could selectively increase tumor uptake of 5-FU.. A syngeneic rat model of colorectal liver metastases was used. Control group rats underwent a 60-s hepatic artery infusion of 14C-5-FU (30 mCi/150 microL). Treatment group rats had vasopressin (60 mIU/kg, dose determined in pilot study) added to the 14C-5-FU infusion. Mean systemic arterial pressure was minimally affected. Tumor:liver (T/L UR) and tumor center:periphery (C/P UR) 5-FU uptake ratios were determined using quantitative autoradiography techniques. Differences in tumor size (< or > 4 mm) and location (superficial vs deep) were accounted for. Statistical analysis was by repeated measures ANOVA (P = 0.01 significant).. A total of 161 tumors in 18 rats was analyzed. T/L URs were significantly higher in the treatment group compared to controls for tumors <4 mm (1.72 +/- 0.14 vs 0.70 +/- 0.16, P <0.001), tumors >4 mm (0.99 +/- 0.15 vs 0.45 +/- 0.16, P = 0.01), deep tumors (1.17 +/- 0.13 vs 0.68 +/- 0.15, P = 0.01), and superficial tumors (1.54 +/- 0. 15 vs 0.47 +/- 0.17, P <0.001). C/P URs did not differ significantly between the groups.. The results of this study show that vasopressin selectively enhances the uptake of 5-FU by colorectal liver metastases in a rat model of hepatic artery infusion. This may represent a promising strategy for improving tumor response rates and patient survival.

Topics: Animals; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Disease Models, Animal; Dose-Response Relationship, Drug; Fluorouracil; Hepatic Artery; Injections, Intra-Arterial; Liver Neoplasms; Male; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents; Vasopressins

Although the majority of colorectal carcinomas express carcino-embryonic antigen (CEA), systemic anti-CEA antibody administration is an ineffective treatment for colorectal liver metastasis. A xenograft model of human colorectal carcinoma in the rat was used to determine anti-CEA antibody uptake into liver metastases. The influence of systemic (iliolumbar vein) or regional (gastroduodenal artery) delivery and effects of regional delivery of histamine, angiotensin II and vasopressin on anti-CEA antibody uptake by metastases were examined. Systemic antibody delivery achieved a median tumour:liver antibody uptake ratio of 1.60 (interquartile range (i.q.r.) 1.02-2.51). Regional delivery resulted in a similar median ratio of 1.61 (i.q.r. 1.22-2.46). Histamine and antibody delivered regionally produced a median tumour:liver ratio of 3.15 (i.q.r. 2.50-4.27), which was significantly greater than that obtained with systemic delivery (P = 0.004). Regional infusion of angiotensin resulted in a median (i.q.r.) ratio of 2.23 (1.58-2.49) and vasopressin in 2.15 (1.41-2.60), values that were not significantly different from those found with systemic or regional delivery alone. When both angiotensin and histamine were infused with antibody, the median tumour:liver ratio was 3.09 (i.q.r. 2.22-4.31), significantly greater than for systemic delivery (P = 0.01) but not significantly different from that obtained following the addition of histamine alone (P = 0.94). Histamine significantly increases antibody uptake in a model of liver metastasis and may improve the effectiveness of targeted immunotherapy in the treatment of colorectal liver metastasis.

Topics: Animals; Antibodies, Neoplasm; Carcinoembryonic Antigen; Colorectal Neoplasms; Histamine; Liver Neoplasms; Neoplasm Transplantation; Rats; Vasopressins