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Articles by S. S. Hecht
Total Records ( 3 ) for S. S. Hecht
  F Kassie , S Kalscheuer , I Matise , L Ma , T Melkamu , P Upadhyaya and S. S. Hecht
 

In previous studies, we reported that indole-3-carbinol (I3C) and myo-inositol (MI) inhibit lung adenoma induced by tobacco smoke carcinogens in A/J mice. In this paper, we extended our work and examined the effects of I3C (70 or 30 µmol/g diet) and MI (56 µmol/g diet) against vinyl carbamate (VC)-induced lung adenocarcinoma by administering the agents from 1 week after the second of two injections of VC until termination of the study at week 18. The higher dose of I3C decreased multiplicities of tumors on the surface of the lung (26%, P = 0.0005), carcinoma incidence (38%), multiplicity (67%, P < 0.0001) and size (complete abolition of carcinoma with an area of >1.0 cm2) as well as adenoma with cellular pleomorphism (46%, P < 0.0001). The lower dose of I3C was less effective. MI decreased multiplicities of pulmonary surface tumors (20%, P = 0.0005), adenoma with cellular pleomorphism (40%, P < 0.0001) and lung adenoma (52%, P < 0.0001) and the proportion of the biggest carcinoma (carcinoma with an area of >1.0 cm2, P < 0.05). Immunoblot analyses of lung tissues for potential target identification showed that I3C (70 µmol/g diet) inhibits IkappaB degradation, nuclear factor-kappaB activation, expression of cyclooxygenase-2, phospho-Akt and fatty acid synthase (FAS) and activates caspase-3 and poly ADP ribose polymerase cleavage. The effect of MI was limited to inhibition of phospho-Akt and FAS expression. Our data show that I3C and MI inhibit lung carcinoma and provide a basis for future evaluation of these compounds in clinical trials as chemopreventive agents for current and former smokers.

  P Upadhyaya , B. R Lindgren and S. S. Hecht
 

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a lung carcinogen in rats and may be a cause of lung cancer in smokers. NNK is metabolized by cytochromes P450 to intermediates that react with DNA forming methyl, pyridyloxobutyl (POB), and pyridylhydroxybutyl (PHB) adducts, which are critical in carcinogenesis. The methyl adduct O6-methylguanine (O6-methyl-G) has miscoding properties, but there are no reports on levels of this adduct in rats treated chronically with NNK in the drinking water, nor has its levels been compared with those of POB- and PHB-DNA adducts. We used liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring to quantify O6-methyl-G in lung and liver DNA of rats treated with a carcinogenic dose of 10 ppm of NNK in the drinking water and sacrificed after 1, 2, 5, 10, 16, and 20 weeks. The maximal level of O6-methyl-G in lung DNA, 2550 ± 263 fmol/mg DNA, was reached at 5 weeks and was significantly greater (P < 0.05) at that point than all other adducts (measured previously) except O2-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine. Overall levels of O6-methyl-G in lung were intermediate between those of total POB- and PHB-DNA adducts. In liver, the wave of O6-methyl-G peaked at 2 weeks while that of total POB-DNA adducts peaked at 10 weeks, and levels of total PHB-DNA adducts were low throughout. The results of this study demonstrate that substantial amounts of O6-methyl-G are formed at various time points in lung and liver DNA of rats treated chronically with NNK, supporting its role in carcinogenesis.

  P Upadhyaya , B. R Lindgren and S. S. Hecht
 

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a lung carcinogen in rats and may be a cause of lung cancer in smokers. NNK is metabolized by cytochromes P450 to intermediates that react with DNA forming methyl, pyridyloxobutyl (POB), and pyridylhydroxybutyl (PHB) adducts, which are critical in carcinogenesis. The methyl adduct O6-methylguanine (O6-methyl-G) has miscoding properties, but there are no reports on levels of this adduct in rats treated chronically with NNK in the drinking water, nor has its levels been compared with those of POB- and PHB-DNA adducts. We used liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring to quantify O6-methyl-G in lung and liver DNA of rats treated with a carcinogenic dose of 10 ppm of NNK in the drinking water and sacrificed after 1, 2, 5, 10, 16, and 20 weeks. The maximal level of O6-methyl-G in lung DNA, 2550 ± 263 fmol/mg DNA, was reached at 5 weeks and was significantly greater (P < 0.05) at that point than all other adducts (measured previously) except O2-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine. Overall levels of O6-methyl-G in lung were intermediate between those of total POB- and PHB-DNA adducts. In liver, the wave of O6-methyl-G peaked at 2 weeks while that of total POB-DNA adducts peaked at 10 weeks, and levels of total PHB-DNA adducts were low throughout. The results of this study demonstrate that substantial amounts of O6-methyl-G are formed at various time points in lung and liver DNA of rats treated chronically with NNK, supporting its role in carcinogenesis.

 
 
 
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