Restricted accessResearch articleFirst published online 2006-9
Oral Glutamine Ameliorates Chemotherapy-induced Changes of Intestinal Permeability and Does not Interfere with the Antitumor Effect of Chemotherapy in Patients with Breast Cancer: A Prospective Randomized Trial
Sixty patients with breast cancer were randomly assigned to oral glutamine or placebo pre-neoadju-vant chemotherapy (CEF regimen).
Methods and Study Design
Oral glutamine supplementation was continued for at least 12 days. Patients kept a daily record of diarrhea and stomatitis. The plasma glutamine level, intestinal permeability (lactulose-mannitol test), and tumor size were analyzed. The expression of Ki-67 and PCNA antigens in breast carcinoma was assessed.
Results
The plasma glutamine level was significantly higher in the glutamine group than in the placebo group (420.39 ± 52.39 mmol/L vs 309.76 ± 42.34 mmoi/L, P <0.05). After one cycle of chemotherapy, the lactulose-mannitol ratio was higher in the placebo group than in the glutamine group (0.0630 ± 0.0091 vs 0.0471 ± 0.0094, P <0.05). No differences were observed in the grades of stomatitis and diarrhea, in the changes in tumor size, and in the expression of Ki-67 and PCNA antigens between the two groups.
Conclusions
Prophylactic oral glutamine could ameliorate the neoadjuvant chemotherapy-induced increase in intestinal permeability, but had no significant positive clinical effect on stomatitis and diarrhea and did not interfere with the antitumor effect of chemotherapy.
ParrilliG., IaffaioliR.V., CapuanoG., BudillonG., BiancoA.R.: Changes in intestinal permeability to lactulose induced by cytotoxic chemotherapy.Cancer Treat Rep,66: 1435–1436, 1982.
2.
DanieleB., PerroneF., GalloC., PignataS., De MartinoS., De VivoR., BarlettaE., TambaroR., AbbiatiR., D'AgostinoL.: Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial.Gut,48: 28–33, 2001.
3.
SukkarS.G., SchenoneE., FoppianiL., NobileM.T.: Experimental assessment of chemotherapy-induced early intestinal damage in colon cancer the lactulose-mannitol permeability test.Tumori,90: 461–463, 2004.
4.
MelicharB., DvorakJ., HysplerR., ZadakZ.: Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents.Chemotherapy,51: 336–338, 2005.
5.
OlaisonG., SjodahlR., TagessonC.: Abnormal intestinal permeability in Crohn's disease: A possible pathogenic factor.Scand J Gastroenterol,125: 321–328, 1990.
6.
De-SouzaD.A., GreeneL.J.: Intestinal permeability and systemic infections in critically ill patients: effect of glutamine.Crit Care Med,33: 1125–1135, 2005.
7.
LiY., LiJ., JiangJ., LiN., WangX., WangZ., WuB., LiuF.: Gly-cyl-glutamine-supplemented long-term total parenteral nutrition selectively improves structure and function in heterotopic small-bowel auto transplantation in the pig.Transpl Int,16: 866–871, 2003.
8.
SiberG.R., MayerR.J., LevinM.J.: Increased gastrointestinal absorption of large molecules in patients after 5-fluorouracil therapy for metastatic colon carcinoma.Cancer Res,40: 3430–3436, 1980.
9.
ParrilliG., IaffaioliR.V., MartoranoM., CuomoR., TafutoS., ZampinoM.G., BudillonG., BiancoA.R.: Effects of anthracy-cline therapy on intestinal absorption in patients with advanced breast cancer.Cancer Res,49: 3689–3691, 1989.
10.
LifschitzC.H., MahoneyD.H.: Low-dose methotrexate-induced changes in intestinal permeability determined by polyethylene glycol polymers.J Pediatr Gastroenterol Nutr,9: 301–306, 1989.
11.
SelbyP.J., LopesN., MundyJ., CroftsM., MillarJ.L., McElwainT.J.: Cyclophosphamide priming reduces intestinal damage in man following high dose melphalan chemotherapy.Br J Cancer,55: 531–533, 1987.
12.
ZieglerT.R., BazarganN., LeaderL.M., MartindaleR.G.: Glutamine and the gastrointestinal tract.Curr Opin Clin Nutr Metab Care,3: 355–362, 2000.
13.
FoxA.D., KripkeS.A., De PaulaJ., BermanJ.M., SettleR.G., RombeauJ.L.: Effect of a glutamine-supplemented enteral diet on methotrexate enterocolitis.JPEN J Parenter Enteral Nutr,12: 325–331, 1988.
14.
GardnerM.L., EarlS.D., WoodD.: Elemental diets in the repair of small intestinal damage.Nutrition,13: 755–975, 1997.
15.
BozzettiF., BiganzoliL., GavazziC., CappuzzoF., CarnaghiC., BuzzoniR., Di BartolomeoM., BajettaE.: Glutamine supplementation in cancer patients receiving chemotherapy: a double-blind randomized study.Nutrition,13: 748–751, 1997.
16.
YoshidaS., KaibaraA., IshibashiN., ShirouzuK.: Glutamine supplementation in cancer patients.Nutrition,17: 766–768, 2001.
17.
AndersonP.M., SchroederM.S., SkubitzK.M.: Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.Cancer,83: 1433–1439, 1998.
18.
LiuF.N., LiJ.S., LiY.S., ShengX.Q., ChenY.M.: Plasma glutamine level monitored with high performance liquid chromatography for patients infusing glutamine after small bowel transplantation.China J Chromatogr,15: 445–446, 1997.
19.
JiangX.H., LiN., LiuF.N.: Measurement of intestinal permeability in healthy Chinese.Parenter Enteral Nutr,8: 233–234, 2001.
BlijlevensN.M.A., van't LandB., DonnellyJ.P., M'RabetL., de PauwB.E.: Measuring mucosal damage induced by cytotoxic therapy.Support Care Cancer,12: 227–233, 2004.
22.
DanieleB., SecondulfoM., De VivoR., PignataS., De Mag-istrisL., DelrioP., PalaiaR., BarlettaE., TambaroR., CarratuR.: Effect of chemotherapy with 5-fluorouracil on intestinal permeability and absorption in patients with advanced colorectal cancer.J Clin Gastroenterol,32: 228–230, 2001.
23.
Fazeny-DornerB., VeitlM., WenzelC., BrodowiczT., ZielinskiC., MuhmM., VogelsangH., MarosiC.: Alterations in intestinal permeability following the intensified polydrug-chemothera-py IFADIC (ifosfamide, adriamycin, dacarbazine).Cancer Chemother Pharmacol,49: 294–298, 2002.
24.
WelshF.K.S., RamsdenC.W., MacLennanK., SheridanM.B., BarclayG.R., GuillouP.J., ReynoldsJ.V.: Gut barrier function in malnourished patients.Gut,42: 396–401, 1998.
25.
JebbS.A., OsborneR.J., MaughanT.S., MohideenN., MackP., MortD., ShelleyM.D., EliaM.: 5-fluorouracil and folinic acid induced mucositis: no effect of oral glutamine supplementation.Br J Cancer,70: 732–725, 1994.
26.
OkunoS.H., WoodhouseC.O., LoprinziC.L., SloanJ.A., LaVasseurB.I., Clemens-SchutjerD., SwanD., AxvigC., EbbertL.P., TironaM.R., MichalakJ.C., PiersonN.: Phase III controlled evaluation of glutamine for decreasing stomatitis in patients receiving fluorouracil (5-FU)-based chemotherapy.Am J Clin Oncol,22: 258–261, 1999.
27.
MuscaritoliM., MicozziA., ConversanoL., MartinoP., PettiM.C., CartoniC., CascinoA., Rossi-FanelliF.: Oral glutamine in the prevention of chemotherapy-induced gastrointestinal toxicity.Eur J Cancer,33: 319–320, 1997.
28.
KlimbergV.S., McClellanJ.L.: Claude H. Organ, Jr. Honorary Lectureship. Glutamine, cancer, and its therapy.Am J Surg,172: 418–424, 1996.
29.
KangY.J., FengY., HatcherE.L.: Glutathione stimulates A549 cell proliferation in glutamine-deficient culture: the effect of glutamate supplementation.J Cell Physiol,161: 589–596, 1994.
30.
BartlettD.L., CharlandS., TorosianM.H.: Effect of glutamine on tumor and host growth.Ann Surg Oncol,2: 71–76, 1995.
31.
ChanceW.T., CaoL., KimM.W., NelsonJ.L., FischerJ.E.: Reduction of tumor growth following treatment with a glutamine antimetabolite.Life Sci,42: 87–94, 1988.
32.
TrihiaH., MurrayS., PriceK., GelberR.D., GolouhR., GoldhirschA., CoatesA.S., CollinsJ., Castiglione-GertschM., GustersonB.A., International Breast Cancer Study Group: Ki-67 expression in breast carcinoma: its association with grading systems, clinical parameters, and other prognostic factors–a surrogate marker?Cancer,97: 1321–1431, 2003.
