Bolus oral glutamine protects rats against CPT-11-induced diarrhea and differentially activates cytoprotective mechanisms in host intestine but not tumor.
Dietary glutamine has been suggested to preserve structural and functional integrity of the gut and high dose bolus glutamine has been hypothesized to protect against potentially fatal endotoxic shock, hyperthermic stress, and side effects of chemotherapy. In this study, we aimed to relate the ability of high dose oral bolus glutamine to mitigate the severe diarrhea induced by 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) chemotherapy to specific cytoprotective mechanisms [heat shock response, glutathione (GSH)] in gut and tumor tissues. Female rats bearing Ward colon tumor received CPT-11 (125 mg x kg(-1) x d(-1)x 3 d) with or without an oral glutamine bolus (0.75 g/kg) administered 30 min prior to each CPT-11 dose. Glutamine reduced incidence and severity of late-onset diarrhea following CPT-11 treatment (P < 0.05) and was associated with potentially beneficial and protective responses in the colon: 1) a 3.1- to 7.2-fold increase of heat shock protein (Hsp)25,-70, and -90alpha (P < 0.05); 2) increased reduced GSH (rGSH):oxidized GSH ratio (P < 0.05); 3) prevention of upregulated activity of a key bacterial enzyme (beta-glucuronidase) in the cecal content that mediates CPT-11 intestinal toxicity (P < 0.05); and 4) increased proportions of CD3+CD8+ lymphocytes and memory CD8+ subset in mesenteric lymph nodes following CPT-11 therapy. By contrast, glutamine treatment did not alter CPT-11's antitumor activity, the amino acid concentrations, Hsp expression, or the ratio of rGSH:oxidized GSH in the tumor. Our data demonstrate a striking dichotomy in the response of tumor and host to oral glutamine administration, concurring with the concept that this nutrient may favorably alter the balance between the host and tumor.
Xue
Hongyu
H
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2.
Sawyer
Michael B
MB
Field
Catherine J
CJ
Dieleman
Levinus A
LA
Murray
David
D
Baracos
Vickie E
VE
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology*; D003967:Diarrhea / Q000517:prevention & control*; D005260:Female; D005973:Glutamine / Q000008:administration & dosage* / Q000627:therapeutic use*; D000077146:Irinotecan; D009374:Neoplasms, Experimental / Q000188:drug therapy; D051381:Rats
D000970:Antineoplastic Agents; D005973:Glutamine; D000077146:Irinotecan; D002166:Camptothecin