Targeted Oral L-Glutamine Treatment of Grades 1, 2, and 3 Oral Mucositis in Adults with Diagnosed Primary Gastrointestinal Malignancy Receiving 5-Fluorouracil (5-FU): A Feasibility Pilot Study

Abstract

PurposeThe purpose of this pilot study was to explore nutritional injury in the context of oral mucositis (OM). It was a beginning look at oral L-glutamine (L-Gln) treatment efficacy through investigation of three "Reaction-to-Nutritional Injury" hypotheses defining OM as a localized secondary nutritional disorder of deficiency (Van Itallie, 1977) resulting from absence of/limited nutritional collateral systems (Kight, 1994):(1) OM severity and human buccal epithelial cell glutamine synthetase (HBEC GS) abundance,(2) HBEC GS abundance and L-Gln treatment, and(3) OM severity and L-Gln treatment.Patients and MethodsThree female colorectal cancer (CRC) outpatients between 61 and 70 years of age receiving FOLFIRI chemotherapy regimen and diagnosed with grades 1 and 2 OM were followed daily throughout treatment cycles and randomly assigned into a two-week mouthwash regimen of 1.0 gm/m2 qid L-Gln or placebo. Treatment crossover occurred every two weeks without defined washout periods. Four controls were recruited as controls for single Western blot (WB) analyses.ResultsOral L-Gln effect on OM severity was statistically significant in all three study participants, although two of the relationships had positive direction. Treatment and OM severity were moderately correlated with a negative direction in one patient. Glutamine appeared to be most efficacious in severe grade 2 OM erythema. Western blot analysis demonstrated absence of HBEC GS activity in cancer patients receiving FOLFIRI treatment for colorectal cancer suggesting competitive inhibition of GS enzyme by chemotherapy. Higher WB bands observed at 55 and 66 kDa may be O-linked glycosylation posttranslational modifications, a possible explanation for the Gln-influenced mechanism of Hsp70 biosynthesis and apoptosis prevention. This may be suggestive of compression of the nutritional injury clinical horizon from stage 4 to stage 1 or 2 where adaptation to absence of/limited nutritional collateral systems theoretically begins after chemotherapy insult. An extended definition of nutritional injury may be the acquired loss of nutritional status at the biomolecular level by way of drug-induced disruption of normal, adaptive metabolic pathways resulting in absence of/limited HBEC GS abundance affecting Gln and Hsp70 availability. This may suggest the need for preemptive L-Gln treatment prior to initiation of a 5-fluorouracil-based chemotherapy regimen.