The candidate, during the prior fellowship training at the UWCCC (years 1+2-clinical training, 3+4-preclinical) has had the opportunity to gain experience in all stage of a research project. Clinical experience was gained as the """"""""phase I fellow"""""""" which involved writing protocols, monitoring the studies, and publishing the results. Due to the candidate's prior work and interest in preclinical drug modulation, research experience was sought in the laboratory of Prof. R.T. Mulcahy, an active member of the Phase I program who has an extensive history of working in the field of experimental therapeutics and drug modulators. Preliminary work examining the glutathione (GSH) redox system has provided valuable experience in tissue culture and molecular biology techniques as well as work with enzyme assays, all necessary to successfully complete the CIA research proposal. Elevations in GSH, a ubiquitous tripeptide, or in GSH S-transferases, a related enzyme, have been found in an increasing number of drug-resistant cell lines. Unfortunately, there has been minimal work exploring the etiology of the increased GSH levels. Is it related to increased biosynthetic enzymatic activity and if so, does this originate at the gene level of post-translationally? Also, could increased expression of a biosynthetic enzyme be a better marker of drug resistance? In order to provide insight into this, the activity of the enzymes of the GSH redox system will be examined in multiple drug-resistant tumor cell lines with elevations in GSH or related enzymes. The human cDNAs for gamma- glutamylcysteine synthase (which was cloned in the Mulcahy lab) and gamma-glutamyl transpeptidase and the necessary biochemical techniques have been successfully used in the Mulcahy lab to initiate studies to hopefully answer these questions. Another important aspect of the proposal is the candidate's role as the study chair of recent and any future clinical trials with Buthionine Sulfoximine (BSO) a modulator of GSH. This provides a unique opportunity to take the observations from the laboratory directly to the clinic or vice versa. The UWCCC Phase I program (a NCI contract awardee for > 10 years) provides an excellent environment to accomplish the clinical aspects of this proposal. The preclinical research would continue to be done in Prof. Mulcahy's laboratory with continued use of UWCCC shared facilities and resources, all of which provide the necessary equipment, space, and personnel to complete the proposal.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA001749-01A1
Application #
3080133
Study Section
Cancer Institutional Fellowship Review Committee (CT)
Project Start
1993-09-30
Project End
1996-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Villodas, Miguel T; Litrownik, Alan J; Newton, Rae R et al. (2016) Long-Term Placement Trajectories of Children Who Were Maltreated and Entered the Child Welfare System at an Early Age: Consequences for Physical and Behavioral Well-Being. J Pediatr Psychol 41:46-54
Villodas, Miguel T; Litrownik, Alan J; Thompson, Richard et al. (2015) Developmental transitions in presentations of externalizing problems among boys and girls at risk for child maltreatment. Dev Psychopathol 27:205-19
Bailey, H H; Ripple, G; Tutsch, K D et al. (1997) Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst 89:1789-96
Mulcahy, R T; Wartman, M A; Bailey, H H et al. (1997) Constitutive and beta-naphthoflavone-induced expression of the human gamma-glutamylcysteine synthetase heavy subunit gene is regulated by a distal antioxidant response element/TRE sequence. J Biol Chem 272:7445-54
Gipp, J J; Bailey, H H; Mulcahy, R T (1995) Cloning and sequencing of the cDNA for the light subunit of human liver gamma-glutamylcysteine synthetase and relative mRNA levels for heavy and light subunits in human normal tissues. Biochem Biophys Res Commun 206:584-9
Mulcahy, R T; Bailey, H H; Gipp, J J (1995) Transfection of complementary DNAs for the heavy and light subunits of human gamma-glutamylcysteine synthetase results in an elevation of intracellular glutathione and resistance to melphalan. Cancer Res 55:4771-5
Bailey, H H; Gipp, J J; Mulcahy, R T (1994) Increased expression of gamma-glutamyl transpeptidase in transfected tumor cells and its relationship to drug sensitivity. Cancer Lett 87:163-70