The use of hematopoeitic stem cell support in conjunction with escalated dose chemotherapy is increasing as therapy for selected malignancies and autoimmune disorders. Effective therapy is hampered by regimen-related toxicities, such as hepatic venocclusive disease (HVOD) and acute lung injury (ALI). Often HVOD precedes the development of ALI and multiple organ failure after BMT. We have recently developed evidence indicating severe, chemotherapy-induced disturbance in the function of the hepatic urea cycle. Baseline urea cycle function has important prognostic significance--patients with inferior urea cycle function have a 10-fold increase in the risk of developing HVOD. We have also discovered a novel, population-based, exonic, single nucleotide polymorphism (SNP) in carbamyl phosphate synthetase-1 (CPS-1), the rate limiting enzyme in urea cycle function. Patients with this SNP have a markedly reduced incidence of HVOD, resolution of ALI if it occurs, and improved short term survival after BMT. We therefore propose a series of studies aimed at expanding our knowledge about the effects of chemotherapy on in vivo urea cycle function. We plan to better define the magnitude and duration of such effects, refine the relative risk estimates for the different CPS-1 SNP genotypes, determine the optimal agent for supporting urea cycle function in vivo, and conduct a Phase II trial of citrulline augmentation in patients undergoing BMT. Parallel in vitro studies will help decipher the mechanisms by which cyclophosphamide alters the function of CPS-1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092313-04
Application #
6796322
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
2001-09-10
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$281,993
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Kallianpur, A R; Hall, L D; Yadav, M et al. (2005) The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 35:1155-64
Kallianpur, Asha R; Hall, Lynn D; Yadav, Meeta et al. (2004) Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer. Cancer Epidemiol Biomarkers Prev 13:205-12