Grant Number:	5R01CA059834-09 Interpret this number
Primary Investigator:	Branch, Robert
Organization:	University Of Pittsburgh At Pittsburgh
Project Title:	Drug Metabolizing Enzymes-Risk Factors in Bladder Cancer
Fiscal Year:	2004

This molecular epidemiology proposal is to continue applying knowledge of pharmacogenomic implications of gene expression of individual drug metabolizing enzymes to assess their role as risk markers for bladder cancer. We propose to use measures of whole body activity for drug metabolizing enzymes using the Pittsburgh cocktail that comprises CYP1A2 (caffeine), CYP2C19 (S-mephenytoin), CYP2D6 (debrisoquine), CYP2E1 (chlorzoxazone) and CYP3A4 (dapsone), as well as mRNA concentrations for each of these CYP enzymes in leukocytes and genotypic identification of known polymorphisms of CYP metabolizing enzymes to include CYP2D6 and CYP2E1. We will assess acetylation using a phenotypic trait measure (dapsone), supplemented by genotyping as well as GSTMI, and GSSTI using genotyping. Our initial work has provided evidence that high activity for CYPD6, low activity of CYP3A4, mutant alleles for acetylation and the null genotype for GSTMI are risk factors for bladder cancer, but to different extent for various forms of this cancer. We have also shown that high CYP2D6 activity is associated with mutations of the retinoblastoma (Rb) gene and low activity of CYP3A4 is independently associated with p53 mutations. Furthermore, different groups of risk factors relate to different mutational spectra of p53. We now propose to extend these observations. Our specific aim is to test the hypothesis that bladder cancer is comprised of a heterogeneous group of diseases in which different groups of associated risk factors relate to disease states that not only vary in etiology, but also in histopathological expression and natural history of the disease. This hypothesis will be evaluated in a case-control study of over 200 patients with incidence presentation of bladder cancer and over 200 controls matched for age, gender and ethnicity, in which environmental and constitutive variables will be related to the disease process. This study will involve a protocol that incorporates an exposure questionnaire, the Pittsburgh cocktail and blood sampling for mRNA quantitation and DNA genotyping. The disease process will be evaluated by clinical assessment and staging, identification of mutations of p53 and Rb genes, blinded histopathological review with grading and following the natural history for the disease. Collectively, these molecular epidemiology studies will improve our understanding of pathogenic mechanisms involved in different forms of bladder cancer and will expand our understanding of the regulation of the gene products that are responsible for drug metabolism in humans.




Genetic polymorphisms in the DNA repair genes XPD and XRCC1, p53 gene mutations and bladder cancer risk.
Authors: Gao W. , Romkes M. , Zhong S. , Nukui T. , Persad R.A. , Smith P.J. , Branch R. , Keohavong P. .
Source: Oncology reports, 2010 Jul; 24(1), p. 257-62.
PMID: 20514470
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Team building: electronic management-clinical translational research (eM-CTR) systems.
Authors: Cecchetti A.A. , Parmanto B. , Vecchio M.L. , Ahmad S. , Buch S. , Zgheib N.K. , Groark S.J. , Vemuganti A. , Romkes M. , Sciurba F. , et al. .
Source: Clinical and translational science, 2009 Dec; 2(6), p. 449-55.
PMID: 20443940
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Exogenous and endogenous determinants of blood trihalomethane levels after showering.
Authors: Backer L.C. , Lan Q. , Blount B.C. , Nuckols J.R. , Branch R. , Lyu C.W. , Kieszak S.M. , Brinkman M.C. , Gordon S.M. , Flanders W.D. , et al. .
Source: Environmental health perspectives, 2008 Jan; 116(1), p. 57-63.
PMID: 18197300
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Evaluation of flurbiprofen urinary ratios as in vivo indices for CYP2C9 activity.
Authors: Zgheib N.K. , Frye R.F. , Tracy T.S. , Romkes M. , Branch R.A. .
Source: British journal of clinical pharmacology, 2007 Apr; 63(4), p. 477-87.
EPub date: 2006-10-19.
PMID: 17054666
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Validation of incorporating flurbiprofen into the Pittsburgh cocktail.
Authors: Zgheib N.K. , Frye R.F. , Tracy T.S. , Romkes M. , Branch R.A. .
Source: Clinical pharmacology and therapeutics, 2006 Sep; 80(3), p. 257-63.
PMID: 16952492
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Bioequivalence revisited: influence of age and sex on CYP enzymes.
Authors: Bebia Z. , Buch S.C. , Wilson J.W. , Frye R.F. , Romkes M. , Cecchetti A. , Chaves-Gnecco D. , Branch R.A. .
Source: Clinical pharmacology and therapeutics, 2004 Dec; 76(6), p. 618-27.
PMID: 15592333
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Coordinated intrahepatic and extrahepatic regulation of cytochrome p4502D6 in healthy subjects and in patients after liver transplantation.
Authors: Carcillo J.A. , Adedoyin A. , Burckart G.J. , Frye R.F. , Venkataramanan R. , Knoll C. , Thummel K. , Roskos L. , Wilson J.W. , Sereika S. , et al. .
Source: Clinical pharmacology and therapeutics, 2003 May; 73(5), p. 456-67.
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Stereoselective determination of the CYP2C19 probe drug mephenytoin in human urine by gas chromatography-mass spectrometry.
Authors: Nolin T.D. , Frye R.F. .
Source: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2003-01-05; 783(1), p. 265-71.
PMID: 12450547
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In vivo modulation of CYP enzymes by quinidine and rifampin.
Authors: Branch R.A. , Adedoyin A. , Frye R.F. , Wilson J.W. , Romkes M. .
Source: Clinical pharmacology and therapeutics, 2000 Oct; 68(4), p. 401-11.
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Use of chlorzoxazone as an in vivo probe of cytochrome P450 2E1: choice of dose and phenotypic trait measure.
Authors: Frye R.F. , Adedoyin A. , Mauro K. , Matzke G.R. , Branch R.A. .
Source: Journal of clinical pharmacology, 1998 Jan; 38(1), p. 82-9.
PMID: 9597564
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All-trans-retinoic acid modulation of drug-metabolizing enzyme activities: investigation with selective metabolic drug probes.
Authors: Adedoyin A. , Stiff D.D. , Smith D.C. , Romkes M. , Bahnson R.C. , Day R. , Hofacker J. , Branch R.A. , Trump D.L. .
Source: Cancer chemotherapy and pharmacology, 1998; 41(2), p. 133-9.
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Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes.
Authors: Frye R.F. , Matzke G.R. , Adedoyin A. , Porter J.A. , Branch R.A. .
Source: Clinical pharmacology and therapeutics, 1997 Oct; 62(4), p. 365-76.
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Clonal analysis of human recurrent superficial bladder cancer by immunohistochemistry of P53 and retinoblastoma proteins.
Authors: Chern H.D. , Becich M.J. , Persad R.A. , Romkes M. , Smith P. , Collins C. , Li Y.H. , Branch R.A. .
Source: The Journal of urology, 1996 Nov; 156(5), p. 1846-9.
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Association of low CYP3A activity with p53 mutation and CYP2D6 activity with Rb mutation in human bladder cancer.
Authors: Romkes M. , Chern H.D. , Lesnick T.G. , Becich M.J. , Persad R. , Smith P. , Branch R.A. .
Source: Carcinogenesis, 1996 May; 17(5), p. 1057-62.
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Improved high-performance liquid chromatographic determination of debrisoquine and 4-hydroxydebrisoquine in human urine following direct injection.
Authors: Frye R.F. , Branch R.A. .
Source: Journal of chromatography. B, Biomedical applications, 1996-02-23; 677(1), p. 178-82.
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The procarcinogen hypothesis for bladder cancer: activities of individual drug metabolizing enzymes as risk factors.
Authors: Branch R.A. , Chern H.D. , Adedoyin A. , Romkes-Sparks M. , Lesnick T.G. , Persad R. , Wilkinson G.R. , Fleming C.M. , Dickinson A.J. , Sibley G. .
Source: Pharmacogenetics, 1995; 5 Spec No, p. S97-102.
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Correlation of polymorphic expression of CYP2D6 mRNA in bladder mucosa and tumor tissue to in vivo debrisoquine hydroxylase activity.
Authors: Romkes-Sparks M. , Mnuskin A. , Chern H.D. , Persad R. , Fleming C. , Sibley G.N. , Smith P. , Wilkinson G.R. , Branch R.A. .
Source: Carcinogenesis, 1994 Sep; 15(9), p. 1955-61.
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