The development of resistance to chemotherapeutic agents by malignant cells remains a significant problem in successful cancer therapy. In vitro analysis of a mechanism which simultaneously conveys resistance to multiple chemotherapeutic agents has been associated with amplification of a specific region of the genome. The techniques of molecular biology, cell biology and recombinant retroviral vectors will be utilized in characterizing this amplified region and the genes overexpressed in multidrug resistant cell lines. Molecular probes from this amplified region will be used to advance our understanding the chemotherapeutic protocols of the future. The practical application of multidrug resistance genes transduced into hematopoetic stem cells will expand our knowledge of hematopoesis and represents the first step towards utilizing hematopoetic stem cells resistant to chemotherapeutic agents as an integral component of chemotherapeutic regimens and bone marrow transplantation.
The specific aims of these studies will be: 1) characterization of the cDNA clones to the gene(s) responsible for multidrug resistance, 2) characterization of the protein(s) encoded by the cDNA clones which are responsible for multidrug resistance, 3) characterization of the mechanism of amplification of multidrug resistance genes, 4) evaluation of children being treated for acute lymphoblastic leukemia for the development of amplification of multidrug resistance gene(s) and its relationship to chemotherapeutic failures, 5) development of in vivo models for the direct analysis of the development of multidrug resistance at the molecular level, 6) construction of a retroviral vector containing the gene responsible for multidrug resistance, and 7) selection in vivo of hematopoetic stem cells carrying the multidrug resistant gene to develop model systems for the analysis of hematopoesis and protection of bone marrow from chemotherapeutic agents.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Wu, C T; Budding, M; Griffin, M S et al. (1991) Isolation and characterization of Drosophila multidrug resistance gene homologs. Mol Cell Biol 11:3940-8
Arceci, R J; Baas, F; Raponi, R et al. (1990) Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus. Mol Reprod Dev 25:101-9
Croop, J M; Raymond, M; Haber, D et al. (1989) The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol 9:1346-50
Greenberger, L M; Croop, J M; Horwitz, S B et al. (1989) P-glycoproteins encoded by mdr 1b in murine gravid uterus and multidrug resistant tumor cell lines are differentially glycosylated. FEBS Lett 257:419-21
Prasanna, H R; Hart, R W; Magee, P N (1989) Effect of dehydroepiandrosterone (DHEA) on the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) in rats. Carcinogenesis 10:953-5
Magee, P N (1989) The experimental basis for the role of nitroso compounds in human cancer. Cancer Surv 8:207-39
Prasanna, H R; Hart, R W; Magee, P N (1989) Effect of food restriction on the metabolism of dimethylnitrosamine (NDMA) in rats. Anticancer Res 9:93-6
Croop, J M; Gros, P; Housman, D E (1988) Genetics of multidrug resistance. J Clin Invest 81:1303-9
Arceci, R J; Croop, J M; Horwitz, S B et al. (1988) The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc Natl Acad Sci U S A 85:4350-4