introduction: polymorphism in genes involved in folate metabolism may cotribute to the susceptibility to acute lymphoblastic leukemia (all). patients and methods : to examine the influence of polymorphism in thymidylate synthase (ts 28-bp repeat) and methionine synthase (ms a2756g) genes on the susceptibility to all, 73 children with all and 128 age and gender matched, unrelated healthy individ...

Aspergillus genus causes many diseases, and the species flavus is highly virulent. Treatment of aspergillosis involves azole derivatives such as voriconazole polyenes amphotericin B. Due to an increase in fungal resistance, treatments are now less effective; search for new compounds with promising antifungal activity has gained importance. The aims this study were evaluate effects synthetic ami...

Using preclinical models of human colon adenocarcinomas in immune-deprived mice, the influence of dose of [6RS]leucovorin ([6RS]LV, 20 to 1000 mg/m2) administered by 24-h i.v. infusion was determined on the following parameters: (a) plasma concentrations of the active [6S] and inactive [6R] isomers of [6RS]LV and the biologically active diastereoisomer of 5-methyltetrahydrolate (5-CH3-H4PteGlu)...

The method for measuring polyglutamate forms of CH2-H4PteGlu and ILtPteGlu, by entrapment in ternary complexes with |6-'H|5-fluoro-2'deoxyuridylate and Lactobacillus casei thymidylate synthase has been characterized. Results demonstrated that (a) the relationship between concentration of ( 11 -1U'M ,ln and complex isolated on nondenaturing gels was dependent upon the number of glutamyl residues...

The broad substrate specificity of herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) has provided the basis for selective antiherpetic therapy and, more recently, suicide gene therapy for the treatment of cancer. We have now constructed an HSV-1 TK mutant enzyme, in which an asparagine (N) residue is substituted for glutamine (Q) at position 125, and have evaluated the effect of this am...

This study describes the regulation of thymidylate synthetase activity in mouse 3T6 fibroblasts during serum-induced transitions between the resting (G0) and growing state. The specific activity of thymidylate synthetase was about 17 times lower in resting 3T6 cells than in exponentially growing cells. When resting cells were serum-stimulated to re-enter the cell cycle, thymidylate synthetase a...

Thymidylate synthetase activity of a human lymphoblastic cell line, CCRF-CEM, was elevated by the addition of methotrexate to the culture medium and was lowered when cytosine arabinoside was added. The simultaneous addition of both drugs resulted in levels of enzyme activity intermediate between those observed for each drug alone. The level of enzyme activity could be modulated by varying the r...

The inhibition of de novo thymidine (dThd) synthesis by the novel folate-based thymidylate synthase (TS) inhibitor ZD1694 (Tomudex) can achieve tumor cell-specific cytotoxicity in vivo. However, nucleosides in the surrounding microenvironment of tumors may be used by the salvage pathway to regenerate any depleted pools, thus providing an efficient mechanism through which to circumvent the ZD169...

HL-60 cells that stably express transfected wild-type (wt) p53 were used to determine whether restoration of wt p53 increased the chemosensitivity of cells that normally lack p53 activity. The wt p53 HL-60 transfectants (SN3 cells) were more sensitive than the parental (S) cells to a number of common anticancer drugs representing various mechanisms of action, whereas HL-60 cells transfected wit...

Thymidylate synthase (TS) catalyzes methylation of dUMP to dTMP and is the target of cancer chemotherapeutic agents (e.g. 5-fluorouracil). Here, we used error-prone PCR to mutagenize the full-length human TS cDNA and then selected mutants resistant to 5-fluorodeoxyuridine in a bacterial complementation system. We found that resistant mutants contained 1-5 amino acid substitutions and that these...