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The effect of maleimide on the metabolism of l -asparagine has been examined in vitro and in viro . In vitro , maleimide is a potent and irreversible inhibitor of the l -asparagine synthetase [ l -glutamine hydrolyzing. (EC 6.3.5.4)] from murine leukemia 5178Y/AR and from murine pancreas; this inhibition is accomplished via sulfhydryl blockade and can be prevented by suitable thiols. In vivo , maleimide was highly irritating locally, producing peritonitis and phlebitis after intraperitoneal and intravenous injection, respectively. The ld 50 in the mouse was 9 mg/kg by the intravenous and intraperitoneal routes; renal, hepatic, neurologic and hematologic toxicities were the principal effects of the drug in this species. l -Asparagine did not alter the lethal effects of maleimide. Maleimide at a dose of 6 mg/kg intraperitoneally did not begin to inhibit pancreatic or tumoral l -asparagine synthetase until 24 hr after its administration: maximum inhibition was delayed until 48–72 hr after dosing. Although maleimide was found to be a potent inhibitor of hepatic l -asparaginase (EC 3.5.1.1) and l -asparagine transaminase (EC 2.6.1.14) in vitro , at no time did the agent inhibit these enzymes in vivo . Additionally, maleimide failed to inhibit protein and nucleic acid synthesis in pancreas and liver, although it did exert a transient repressive effect on these processes in subcutaneous L5178Y/AR tumor. The drug was a potent cytotoxin to 12L1210 cells in culture, causing partial arrest in the G 2 phase of the cell cycle as well as general slowing of progression through the cell cycle. No therapeutic action was produced vs this tumor growing in the peritoneum of mice nor was the drug effective vs subcutaneous L5178Y or L5178Y/AR. However, when maleimide was used to wash the surgical wound created by extirpation of Lewis Lung Carcinoma growing in the muscles of the hind limb, the drug did inhibit local recurrence of tumor, most notably when used in conjunction with parenteral cyclophosphamide. It is concluded that maleimide is an inhibitor, in vitro , of the enzymes of l -asparagine metabolism because of its ability to form covalent bonds with critical sulfhydryl compounds. |
