In this grant application we address major differences which we have documented in the metabolism of vitamin B6 in neoplastic cells as contrasted to their normal counterparts. In particular, pyridoxine 5'- phosphate oxidase (PNPO), the rate limiting enzyme in the synthesis of the active form of vitamin B6 (i.e., pyridoxal 5'-phosphate; PLP) is absent in certain liver and neurally-derived tumors and cell lines. In addition, the activity of pyridoxal kinase (PLK) which is also involved in the biosynthesis of PLP, is variably altered in tumor cells. The absence of PNPO and the alterations in PLK activity in tumor cells signify major perturbations of PLP, may be important players in the progression towards the neoplastic phenotype. We further hypothesize that the absence of PNPO protein and enzyme activity in tumor cells may be taken advantage of in the diagnosis/prognosis of cancers. We propose to address the hypotheses described above by accomplishing the following specific aims: 1. Generate antibodies to purified PNPO and PLK proteins and isolate their corresponding complimentary DNAs from a rat liver cDNA library 2. Elucidate the molecular mechanism(s) responsible for the absence of PNPO in tumors 3. Evaluate the effects of PNPO and PLK expression on tumor cell growth in vitro and in vivo for determination of possible alternate/novel pathways of PLP biosynthesis Accomplishing these specific aims will aid in realization of our long term objectives, which are a) to better understand the regulation of vitamin B6 metabolism in cancer and development and b) to take advantage of differences in B6 metabolism between cancer cells and their normal cell counterparts diagnostically and possibly therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073887-02
Application #
2882478
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
1998-03-01
Project End
2001-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455