ABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , Colonic Neoplasms/drug therapy , Fluorouracil/pharmacology , Folic Acid/pharmacology , Methotrexate/pharmacology , gamma-Glutamyl Hydrolase/antagonists & inhibitors , Adenocarcinoma/drug therapy , Adenocarcinoma/enzymology , Animals , Breast Neoplasms/enzymology , Cell Line, Tumor , Colonic Neoplasms/enzymology , Drug Screening Assays, Antitumor , Female , Fluorouracil/administration & dosage , Folic Acid/administration & dosage , HCT116 Cells , Humans , Male , Methotrexate/administration & dosage , Mice , Mice, Inbred BALB C , Mice, Nude , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Transfection , Xenograft Model Antitumor Assays , gamma-Glutamyl Hydrolase/genetics , gamma-Glutamyl Hydrolase/metabolismABSTRACT
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.
