RÉSUMÉ
BACKGROUND: γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect. METHODS: We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo. RESULTS: Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased. CONCLUSION: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Tumeurs du sein/traitement médicamenteux , Tumeurs du côlon/traitement médicamenteux , Fluorouracil/pharmacologie , Acide folique/pharmacologie , Méthotrexate/pharmacologie , Gamma-glutamyl hydrolase/antagonistes et inhibiteurs , Adénocarcinome/traitement médicamenteux , Adénocarcinome/enzymologie , Animaux , Tumeurs du sein/enzymologie , Lignée cellulaire tumorale , Tumeurs du côlon/enzymologie , Tests de criblage d'agents antitumoraux , Femelle , Fluorouracil/administration et posologie , Acide folique/administration et posologie , Cellules HCT116 , Humains , Mâle , Méthotrexate/administration et posologie , Souris , Souris de lignée BALB C , Souris nude , Petit ARN interférent/administration et posologie , Petit ARN interférent/génétique , Transfection , Tests d'activité antitumorale sur modèle de xénogreffe , Gamma-glutamyl hydrolase/génétique , Gamma-glutamyl hydrolase/métabolismeRÉSUMÉ
The treatment of patients with anterior abdominal stab wounds remains controversial. We reserve celiotomy for patients who have clinical findings of peritonitis or hemorrhage. Repeated physical examination is the most important element of observation. Recently, 330 patients with stable abdominal stab wounds presented over a 12-month period. These patients were followed up with serial physical examinations and laboratory measurements. Of the 330 patients, 107 patients (32%) required celiotomy for the repair of a life-threatening injury (group 1); 28 patients (8%) underwent nontherapeutic celiotomies (group 2); 19 patients (6%) had negative explorations (group 3); and 176 patients (53%) were observed and discharged (group 4). There were three missed injuries in group 4. Serial physical examination can be a reliable technique in the management of abdominal stab wounds and is comparable to other approaches.