Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284).

Cdc25 protein phosphatases are regulators of cyclin-dependent kinases and are often highly expressed in human malignancies. Few small molecule inhibitors of the Cdc25 phosphatase family have been identified and little is known about their disposition, metabolism or efficacy in xenograft models. In this study, the efficacy, pharmacokinetics, and metabolism of a potent quinolinedione Cdc25 phosphatase inhibitor, DA3003-1, in mice was examined.

Role of NQO1 polymorphisms as risk factors for squamous cell carcinoma of the head and neck.

A case: control study was carried out to determine if inactivating polymorphisms of the NQO1 gene at bases 609 and 465 are associated with altered risk of developing squamous cell carcinoma of the head and neck (SCCHN). Genotyping was carried out by PCR RFLP analysis on whole blood samples. The frequency of the inactive 609T and active 609C forms, and the inactive 465T and active 465C forms, of NQO1 were compared in patient and control groups by a logistic regression analysis and odds ratios (ORs) were calculated.

Crystal structure of human glutathione S-transferase A3-3 and mechanistic implications for its high steroid isomerase activity.

The crystal structure of human class alpha glutathione (GSH) S-transferase A3-3 (hGSTA3-3) in complex with GSH was determined at 2.4 A. Despite considerable amino acid sequence identity with other human class alpha GSTs (e.

Distribution of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase.

Purpose: In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FAU) that are activated by thymidylate synthase. These studies were designed to evaluate FAU as a potential therapeutic and diagnostic probe.

In vitro metabolism of the phosphatidylinositol 3-kinase inhibitor, wortmannin, by carbonyl reductase.

The phosphatidylinositol 3-kinase inhibitor, wortmannin, is extensively used in molecular signaling studies and has been proposed as a potential antineoplastic agent. The failure to detect wortmannin in mouse plasma after i.v.

NAD(P)H:quinone oxidoreductase-1-dependent and -independent cytotoxicity of potent quinone Cdc25 phosphatase inhibitors.

Cdc25 dual-specificity phosphatases coordinate cell cycle progression and cellular signaling. Consequently, Cdc25 inhibitors represent potential anticancer agents. We evaluated >10,000 compounds for inhibition of human Cdc25 phosphatases and identified many potent and selective inhibitors, which all contained a quinone.

Use of high-performance liquid chromatography to characterize the rapid decomposition of wortmannin in tissue culture media.

Although wortmannin is extensively used in molecular signaling studies, its stability in tissue culture medium has not been assessed precisely. Therefore, we used high-performance liquid chromatography (HPLC) and mass spectrometry (MS) to characterize the decomposition of wortmannin in five commonly used media. Wortmannin was added to medium alone or to medium supplemented with 10% unheated or heat-inactivated fetal bovine serum and incubated at 37 degrees C.

Exceptional activity of murine glutathione transferase A1-1 against (7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-induced DNA damage in stably transfected cells.

We have shown previously that the alpha class murine glutathione transferase (GST) isoenzyme mGSTA1-1, unlike other mammalian class alpha GSTs, is highly efficient in catalyzing the glutathione (GSH) conjugation of (7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], which is the ultimate carcinogenic metabolite of benzo[a]pyrene. The present studies were undertaken to determine the efficacy of mGSTA1-1 in cellular protection against (+)-anti-BPDE-induced DNA damage in HepG2 cells stably transfected with mGSTA1 cDNA. Untransfected HepG2 cells, vector-transfected HepG2 cells (HepG2-vector), and cells transfected with mGSTA4 cDNA (HepG2-mGSTA4), an alpha class murine GST isoenzyme with low (+)-anti-BPDE-GSH conjugating activity, were used as controls for comparison.

Implication of alternative splicing for expression of a variant NAD(P)H:quinone oxidoreductase-1 with a single nucleotide polymorphism at 465C>T.

Three alleles of the human reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1 (NQO1) gene are known; wild-type, 609C>T variant, and 465C>T variant; designated as NQO1*1 and NQO1*2, and NQO1*3, respectively. Previously, we found NQO1*3 in one allele of HCT-116 cells, and in both alleles of the mitomycin C-resistant subline, HCT-116R30A. The NQO1 protein content of HCT-116R30A is 5% that of HCT-116.