Selective inhibition of a plasma fucosyltransferase by N-ethylmaleimide.
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Biomedical subjects
Publications and source records attributed to D Kessel.
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Levels of glycoprotein:sialyltransferase activity (EC 2.4.99.1; CMP-acetyl-neuraminate:D-galactosyl-glycoprotein N-acetylneuraminyl-transferase) were measured in plasma of patients with neoplastic disease, and were found elevated above normal control values in 85% of patients examined. There was a correlation between enzyme levels and course of disea-e in 46 of 57 patients studied serially during therapy. Plasma sialyltransferase may be a useful marker enzyme for monitoring effectiveness of therapeutic programs for disseminated neoplasms.
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Elevated levels of three plasma glycosyltransferases were associated with neoplasia in cancer patients, notably those with tumor metastatic to liver. We examined levels of sialyltransferase, galactosyltransferase, and fucosyltransferase in metastatic tumor and apparently uninvolved host liver tissue in attempts to delineate possible sources of elevated plasma enzyme levels. Highest levels of fucosyltransferase activity were found associated with tumor tissue; in contrast, sialyltransferase and galactosyltransferase activity was often highest at the tumor-liver interface.
We have measured plasma levels of an alpha-2-L-fucosyltransferase in 18 patients with acute adult leukemia at various clinical stages along with simultaneous bone marrow aspirations and biopsies. Patients in remission had significantly lower levels of this enzyme than did nonresponding or relapsing patients. Furthermore, plasma levels were correlated with percentage of marrow blast cells. This enzyme may serve as a biological marker for monitoring patients with acute leukemia receiving chemotherapy. It is particularly helpful as a guide to chemotherapy in patients on whom bone marrow aspirates are technically difficult to obtain.
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Levels of plasma sialyltransferase were measured in a patient with disseminated carcinoma of the testes. Initial enzyme values, elevated six fold above those in normal controls, were among the highest thus far encountered in a population of patients with various stages and types of malignancy. During a remarkable respose to chemotherapy with cis-diaminodichloroplatinum, plasma sialyltransferase levels fell markedly. Serial measurement of this enzyme may aid in evaluation of tumor responsiveness to therapy in patients whose disease is not readily measurable.
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Sialyltransferase activity was measured in plasma samples using desialated fetuin as the acceptor and cytidine 5'-phosphate-sialic acid as donor. The data show an increased enzyme level in 56 of 65 cancer patients studied, as compared with normal control values. The enzyme was not significantly elevated during lacation or in liver cirrhosis, but it was elevated in rheumtoid arthritis. Of the patients with cancer, 35 showed plasma enzyme levels above any value encountered in rheumatoid arthritis plasmas. The determinants of enzyme level in cancer appear to be complex: monitoring of plasma sialytransferase may be of value in measuring tumor progression, metatastatic involvement, or success of therapeutic programs.
The S isomer of Ftorafur was synthesized and the ability of the latter to inhibit growth of cultured human fibroblasts was determined relative to both the R isomer and the racemic mixture (Ftorafur) that is presently used clinically. No significant difference in the cytotoxic effects or the relative abilities to prevent an increase in cell numbers was observed with the three forms. Inhibition of DNA synthesis in murine L1210 leukemia cells by either isomer was observed only after prolonged (18-hr) exposure. The data suggest that Ftorafur is a repository form of 5-fluorouracil and that activity is manifested equally by both isomers.
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A series of benzo-2,1,3-oxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) inhibit incorporation of precursors into nucleic acids and protein by murine leukemia cells. At slighly higher levels, substantial single- and double-strand DNA breakage was observed. At still higher concentrations, inhibition of phosphorylation of uridine and thymidine was found. Structure-activity relationships show that only compounds bearing appropriate substitutions at positions 4 and 7 were effective inhibitors of biosynthetic pathways. Such compounds appear to interact with a wide variety of biological systems and may be useful in elucidating modes of macromolecule synthesis.
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