Structure Effect on Antioxidant Activity of Catecholamines toward Singlet Oxygen and Other Reactive Oxygen Species in vitro.

The reactivity of catecholamine neurotransmitters and the related metabolites were precisely investigated toward 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and reactive oxygen species. Catecholamines reacted immediately with DPPH radicals, their reactivity being stronger than that of ascorbic acid as a reference. Superoxide scavenging activities of catecholamines determined by WST-1 and electron spin resonance (ESR) spin trapping methods were also high. Whereas tyrosine, the dopamine precursor showed no reactivity toward superoxide. The reactivity toward singlet oxygen was evaluated by observing specific photon emission from singlet oxygen. The results revealed that reactivity of catecholamines was markedly higher than that of sodium azide, and catechin as catechol reference. The reaction of catecholamines and singlet oxygen was further studied by ESR using 55-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping reagent and rose bengal as photosensitizer. DMPO-OH signal of epinephrine was significantly small compared to other catecholamines, catechin, and 4-methylcatechol as a reference compound and was as small as that of tyrosine. The signal formation was totally dependent on singlet oxygen, and the presence of catechol compounds. These results indicated that epinephrine is the most potent singlet oxygen quencher than other catecholamines, and the secondary amino group in its alkyl side chain could play a role in unique singlet oxygen quenching property of epinephrine.

Factors regulating tumor pressure in cases of small hepatocellular carcinoma.

BACKGROUND/AIMS: There is scare information regarding tumor pressure in hepatocellular carcinoma. As the tumor diameter increases, histological manifestations become more diverse. Therefore, studies based on relatively small tumors are needed in order to search for those underlying factors that are directly related to tumor pressure in hepatocellular carcinoma. The purpose of this study was to determine which factors regulate tumor pressure in cases of hepatocellular carcinoma where the diameter of the tumor is 3cm or less. METHODOLOGY: The study included 54 patients with small hepatocellular carcinoma in whom tumor pressure had been determined and in whom the tumor had been confirmed histologically. Tumor pressure was determined percutaneously under ultrasonographic guidance. RESULTS: Hepatic tissue pressure (p = 0.01), tumor size (p < 0.01), number of tumors (p = 0.01), degree of tumor differentiation (p < 0.01), ultrasonographic halo (p < 0.01), angiographic tumor staining (p < 0.01) and angiographic tumor vessel (p = 0.03) all showed significant correlation with tumor pressure. Multivariate analysis revealed that angiographic tumor staining (p = 0.001), hepatic tissue pressure (p = 0.013), and tumor size (p = 0.044) were significant factors associated with tumor pressure. CONCLUSIONS: It was suggested that tumor pressure in small hepatocellular carcinoma was mainly regulated through development of the neovasculature.

Hydrogen abstraction from neurotransmitters by active oxygen species facilitated by intramolecular hydrogen bonding in the radical intermediates.

The reactivity of neurotransmitters toward hydrogen abstraction by an active oxygen species (the cumylperoxyl radical) is comparable to that of a strong antioxidant such as catechin due to the strong intramolecular hydrogen bonding, which has been successfully detected by ESR.

[A case of colon cancer with liver metastases and lymph node metastases successfully treated with surgery followed by CPT-11 and 5-FU chemotherapy].

A sixty-year-old woman underwent right hemicolectomy and D2 lymph node dissection. However, a solitary liver metastasis and para-aortic lymph node metastasis were detected three months after surgery. Chemotherapy using CPT-11 and 5-FU (civ) was immediately performed. After one course of this regimen, the chemotherapeutic effect was evaluated as a partial response (PR) in the liver metastasis, and as a complete response (CR) in the para-aortic lymph node. There was a massive therapeutic effect without side effects. Two further courses of chemotherapy were performed after changing from 5-FU to 5'-DFUR. Both regions of metastasis (liver and lymph nodes) continue to exhibit CR and the patient is free from any symptoms almost one year after surgery. The authors believe that this regimen is very effective and will contribute quality of life in advanced colon cancer patients.

M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis.

BACKGROUND: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. METHODS: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. RESULTS: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. CONCLUSIONS: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy.

Synthesis and characterization of a series of (hydroperoxo)-, (alkylperoxo)-, and (mu-peroxo)palladium complexes containing the hydrotris(3,5-diisopropylpyrazolyl)borato ligand (Tp(iPr2)): (Tp(iPr2))(py)Pd-OO-X [X = H, t-Bu, Pd(Tp(iPr2))(py)] and (Tp(iPr2))(py)Pd-(mu-kappa(1):kappa(2)-OO)-PdTp(iPr2).

Dehydrative condensation of the hydroxopalladium complex (Tp(iPr2))(py)Pd-OH (1) with hydroperoxides (XOOH: X = H, t-Bu) produces the corresponding (hydroperoxo)-, (Tp(iPr2))(py)Pd-OOH (2a), and (tert-butylperoxo)palladium complexes, (Tp(iPr2))(py)Pd-OOBu(t) (3). Treatment of 2a with PPh(3) results in concomitant ligand displacement giving (Tp(i)(Pr2))(Ph(3)P)Pd-OOH (2b) and oxygenation of PPh(3) giving O=PPh(3). Further condensation between 1 and 2a gives the mu-kappa(1):kappa(1)-peroxo complex (Tp(iPr2))(py)Pd-OO-Pd(Tp(iPr2))(py) (4), while condensation between the bis(mu-hydroxo)dipalladium complex (PdTp(iPr2))(2)(mu-OH)(2) (7) with 2a affords the unsymmetrical mu-kappa(1):kappa(2)-peroxo complex (Tp(iPr2))(py)Pd-OO-PdTp(iPr2) (5). These peroxopalladium complexes 2-5 have been fully characterized by a combination of spectroscopic and crystallographic analyses, which lead to description of the O-O moieties in these complexes as peroxide (O(2)(2-)) with sp(3)-hybridized oxygen atoms. The OOH moiety in 2b is found to interact with the noncoordinated nitrogen atom of the pendant pyrazolyl group through hydrogen bond. The O(2) moieties in 2-5 turn out to be so nucleophilic (basic) as to add across carbon-heteroatom multiple bonds in acetonitrile and acetaldehyde to give the peroxometallacycle Tp(iPr2)Pd[OOC(Me)=N)]Pd(iPr2)(py)(8) (from 2, 4, and 5) and the acetato complex (Tp(iPr2))(py)Pd-OC(=O)CH(3) (9) (from 2-4), respectively. Methyl vinyl ether and styrene, CH(2)=CHY (Y = OMe, Ph), are converted to the corresponding methyl ketones, CH(3)C(=O)Y, upon treatment with 2-4.

M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan.

Mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) tumor suppressor- gene mutation is an early event in human hepatocellular carcinoma (HCC) formation in the United States, but its role in hepatocarcinogenesis in Japan is unclear. We therefore determined M6P/IGF2R mutation frequency in HCCs from patients who resided in the southern, central, and northern regions of Japan. Ten single nucleotide polymorphisms were used to identify HCCs and dysplastic liver nodules with M6P/IGF2R loss of heterozygosity. The retained allele in these tumors was also assessed for point mutations and deletions in the M6P/IGF2R ligand binding domains by direct sequencing of polymerase chain reaction (PCR) amplified DNA products. Fifty-eight percent (54 of 93) of the patients were heterozygous at the M6P/IGF2R locus, and 67% (43 of 64) of the HCCs and 75% (3 of 4) of the dysplastic nodules had loss of heterozygosity. The remaining allele in 21% of the HCCs contained either M6P/IGF2R missense mutations or deletions, whereas such mutations were not found in the dysplastic lesions. In conclusion, M6P/IGF2R is mutated in HCCs from throughout Japan with a frequency similar to that in the United States. Loss of heterozygosity in dysplastic liver nodules provides additional evidence that M6P/IGF2R haploid insufficiency is an early event in human hepatocarcinogenesis.

Synthesis and Characterization of the Benzoylformato Ferrous Complexes with the Hindered Tris(pyrazolyl)borate Ligand as a Structural Model for Mononuclear Non-Heme Iron Enzymes.

By using a hindered tripodal ligand, hydrotris(3-tert-butyl-5-isopropylpyrazol-1-yl)borate HB(3-tBu-5-iPrpz)(3), a series of monomeric ferrous complexes having acetate, hydroxide, and benzoylformate ligands were synthesized. Reaction of KHB(3-tBu-5-iPrpz)(3) with anhydrous Fe(OAc)(2) yielded acetato complexes Fe(OAc)[HB(3-tBu-5-iPrpz)(3)] (1) and Fe(OAc)[HB(3-tBu-5-iPrpz)(3)](3-iPr-5-tBupzH) (2). A hydroxo complex Fe(OH)[HB(3-tBu-5-iPrpz)(3)] (3) was prepared by the treatment of 1 or 2 with aqueous NaOH. The geometry of Fe(II) in 3 is a slightly distorted tetrahedron as determined by X-ray crystallography. The hydroxo complex 3 reacted with benzoylformic acid to give the benzoylformato complex Fe(O(2)CC(O)Ph)[HB(3-tBu-5-iPrpz)(3)] (4), which showed thermochromism which depended on the coordination geometry of the benzoylformate ligand. The Fe(II) ion in the colorless form of 4 isolated at 4 degrees C is coordinated by a tetrahedral N(3)O(1) ligand donor set including the unidentate benzoylformato ligand. On the other hand, the bluish purple form of 4 isolated at -20 degrees C has a five-coordinate trigonal bipyramidal Fe(II) center. The benzoylformate ligand in this bluish purple form works as a chelate ligand through coordination of the unidentate carboxylate oxygen atom as well as the ketonic oxygen atom. A benzoylformato complex containing an additional pyrazole, Fe(O(2)CC(O)Ph)[HB(3-tBu-5-iPrpz)(3)](3-iPr-5-tBupzH) (5), was obtained by the reaction of 3 with benzoylformic acid in the presence of 3-tert-butyl-5-isopropylpyrazole. The iron atom in 5 is coordinated by an N(4)O(1) ligand donor set with trigonal bipyramidal geometry. A hydrogen-bonding interaction between the carboxylate oxygen atom and the additional pyrazole's NH proton in 5 is suggested from the short distance between O(carboxylate) and N(pyrazole) observed in the X-ray structure and the absence of the nuNH vibration in the IR spectrum.