Abstract

The applicant's laboratory has recently identified a transport system for the epipodophyllotoxins which is not shared by other drugs generally included in the multi-drug resistance phenotype. The overall aims of this research proposal are to investigate the role of this transporter in VP-16 resistance, to discover ways to increase the effectiveness of VP-16 and to overcome VP-16 resistance through biochemical and molecular characterization of mechanisms of resistance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066739-02
Application #
2390868
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1996-04-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Murren, John R; Pizzorno, Giuseppe; DiStasio, Susan A et al. (2002) Phase I study of perillyl alcohol in patients with refractory malignancies. Cancer Biol Ther 1:130-5
Murren, J R; DiStasio, S A; Lorico, A et al. (2000) Phase I and pharmacokinetic study of novobiocin in combination with VP-16 in patients with refractory malignancies. Cancer J 6:256-65
Rappa, G; Shyam, K; Lorico, A et al. (2000) Structure-activity studies of novobiocin analogs as modulators of the cytotoxicity of etoposide (VP-16). Oncol Res 12:113-9
Rappa, G; Murren, J R; Johnson, L M et al. (2000) Novobiocin-induced VP-16 accumulation and MRP expression in human leukemia and ovarian carcinoma cells. Anticancer Drug Des 15:127-34
Rappa, G; Finch, R A; Sartorelli, A C et al. (1999) New insights into the biology and pharmacology of the multidrug resistance protein (MRP) from gene knockout models. Biochem Pharmacol 58:557-62
Lorico, A; Rappa, G; Finch, R A et al. (1997) Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res 57:5238-42
Cory, J G; Cory, A H; Lorico, A et al. (1997) Altered efflux properties of mouse leukemia L1210 cells resistant to 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone. Anticancer Res 17:3185-93
Rappa, G; Lorico, A; Liu, M C et al. (1997) Overexpression of the multidrug resistance genes mdr1, mdr3, and mrp in L1210 leukemia cells resistant to inhibitors of ribonucleotide reductase. Biochem Pharmacol 54:649-55
Rappa, G; Lorico, A; Flavell, R A et al. (1997) Evidence that the multidrug resistance protein (MRP) functions as a co-transporter of glutathione and natural product toxins. Cancer Res 57:5232-7
Lorico, A; Rappa, G; Flavell, R A et al. (1996) Double knockout of the MRP gene leads to increased drug sensitivity in vitro. Cancer Res 56:5351-5