The development of drug resistance in leukemia cells constitutes the major reason for treatment failure in acute myeloid leukemia (AML). Although a number of prognostic factors such as cellular morphology and cytogenetic abnormalities have been identified, the mechanisms by which cellular resistance to chemotherapy occurs are poorly understood. Because even unsuccessful regimens produce substantial cytoreduction, it is likely that characteristics of subpopulations of leukemic cells will be of importance in the development of resistance. The University of Maryland Cancer Center (UMCC) will perform multiple laboratory studies on leukemic blasts to simultaneously evaluate a number of proposed mechanisms in vitro. These results will be correlated with outcome after treatment and clinical parameters in a consecutive cohort of newly diagnosed patients treated on clinical trials. Serial evaluations will be done at the time of treatment failure or relapse. We propose to focus on: cellular and pharmacokinetic mechanisms of resistance of daunorubicin with assessment of the multidrug resistance phenotypes associated with p-glycoprotein and topoisomerase II abnormalities in leukemia cells; evaluation of methods for determination of drug sensitivity; in vitro and subsequent in vivo evaluation of non- cytotoxic modulaters of p-glycoprotein function. Flow cytometry, molecular hybridization and immunologic techniques will be utilized to identify these various parameters in subpopulations of leukemic cells. The UMCC has a large population of leukemia patients, extensive preliminary data on the proposed projects, a history of productive clinical-laboratory interactions and represents an excellent environment in which to study these important questions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA052178-01
Application #
3196967
Study Section
Special Emphasis Panel (SRC (55))
Project Start
1990-05-01
Project End
1993-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Natarajan, Karthika; Xie, Yi; Baer, Maria R et al. (2012) Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol 83:1084-103
Bauer, Kenneth S; Karp, Judith E; Garimella, Tushar S et al. (2005) A phase I and pharmacologic study of idarubicin, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia. Leuk Res 29:263-71
Ross, D D; Karp, J E; Chen, T T et al. (2000) Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood 96:365-8
Ross, D D; Yang, W; Abruzzo, L V et al. (1999) Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J Natl Cancer Inst 91:429-33
Doyle, L A; Yang, W; Abruzzo, L V et al. (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A 95:15665-70
Ross, D D; Gao, Y; Yang, W et al. (1997) The 95-kilodalton membrane glycoprotein overexpressed in novel multidrug-resistant breast cancer cells is NCA, the nonspecific cross-reacting antigen of carcinoembryonic antigen. Cancer Res 57:5460-4
Doyle, L A; Yang, W; Rishi, A K et al. (1996) H19 gene overexpression in atypical multidrug-resistant cells associated with expression of a 95-kilodalton membrane glycoprotein. Cancer Res 56:2904-7
Doyle, L A; Ross, D D; Sridhara, R et al. (1995) Expression of a 95 kDa membrane protein is associated with low daunorubicin accumulation in leukaemic blast cells. Br J Cancer 71:52-8
Ross, D D; Doyle, L A; Yang, W et al. (1995) Susceptibility of idarubicin, daunorubicin, and their C-13 alcohol metabolites to transport-mediated multidrug resistance. Biochem Pharmacol 50:1673-83
Ross, D D; Wooten, P J; Tong, Y et al. (1994) Synergistic reversal of multidrug-resistance phenotype in acute myeloid leukemia cells by cyclosporin A and cremophor EL. Blood 83:1337-47

Showing the most recent 10 out of 12 publications