A major problem in cancer chemotherapy remains the development of tumor cell resistance to multiple chemotherapeutic agents. Overexpression of the multidrug resistance gene (MDR1) leads to the appearance of P- glycoprotein (P-gp) in the plasma membrane of tumor cells. This protein functions as a drug efflux pump resulting in tumor cell resistance to many cytotoxic drugs. The long-term objectives of this grant proposal are (1) to further understand the structural determinants and biochemical characteristics of P-gp, and (2) to unravel the molecular mechanism by which P-gp can recognize a wide variety of lipophilic agents including both cytotoxic drugs and MDR modulators.
The specific aims of this proposal are to (1) synthesize specific photoaffinity probes, (2) investigate the modes of drug interaction with P-gp, (3) identify drug binding domains of P-gp, and (4) purify drug binding fragments of P-gp and identify the specific amino acid sequences of the drug binding site(s). These studies will increase our knowledge of the biochemistry and molecular nature of P-gp and could provide a framework for the rational design and synthesis of effective MDR modulators.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA056078-01
Application #
3200569
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1992-05-01
Project End
1995-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Safa, Ahmad R; Pollok, Karen E (2011) Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers (Basel) 3:1639-71
Park, Soo-Jung; Wu, Ching-Huang; Choi, Mi-Ran et al. (2006) P-glycoprotein enhances TRAIL-triggered apoptosis in multidrug resistant cancer cells by interacting with the death receptor DR5. Biochem Pharmacol 72:293-307
Safa, Ahmad R (2004) Identification and characterization of the binding sites of P-glycoprotein for multidrug resistance-related drugs and modulators. Curr Med Chem Anticancer Agents 4:1-17
Wu, Ching-Huang; Gordon, John; Rastegar, Mojgan et al. (2002) Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant. Oncogene 21:5160-74
Ogretmen, B; Safa, A R (2000) Identification and characterization of the MDR1 promoter-enhancing factor 1 (MEF1) in the multidrug resistant HL60/VCR human acute myeloid leukemia cell line. Biochemistry 39:194-204
Ogretmen, B; Barredo, J C; Safa, A R (2000) Increased expression of lung resistance-related protein and multidrug resistance-associated protein messenger RNA in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 22:45-9
Ogretmen, B; Safa, A R (1999) Negative regulation of MDR1 promoter activity in MCF-7, but not in multidrug resistant MCF-7/Adr, cells by cross-coupled NF-kappa B/p65 and c-Fos transcription factors and their interaction with the CAAT region. Biochemistry 38:2189-99
Ogretmen, B; McCauley, M D; Safa, A R (1998) Molecular mechanisms of loss of beta 2-microglobulin expression in drug-resistant breast cancer sublines and its involvement in drug resistance. Biochemistry 37:11679-91
Ogretmen, B; Bahadori, H; McCauley, M et al. (1998) Lack of correlation of MRP and gamma-glutamylcysteine synthetase overexpression with doxorubicin resistance due to increased apoptosis in SV40 large T-antigen-transformed human mesothelial cells. Cancer Chemother Pharmacol 42:441-6
Ogretmen, B; Bahadori, H R; McCauley, M D et al. (1998) Co-ordinated over-expression of the MRP and gamma-glutamylcysteine synthetase genes, but not MDR1, correlates with doxorubicin resistance in human malignant mesothelioma cell lines. Int J Cancer 75:757-61

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