Reduced Folate Transport and Antifolate Resistance

Melera, Peter William

Abstract

This project is focused upon determining the molecular genetic basis for alterations in transport that render cells resistant to antifolates by preventing drug accumulation. A full length cDNA will be cloned by preparing an expression library from the Chinese hamster lung cell line DC- 3F/FA3 that appears to overexpress a gene for a 43.2 kd glycoprotein associated with enhanced folate uptake. Functional interactions of this and the hp58 gene product will be studied and used to isolate putative mutant transporters from existing cell lines.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Research Project (R01)
• Project #: 5R01CA049538-07
• Application #: 2442974
• Study Section: Experimental Therapeutics Subcommittee 1 (ET)
• Project Start: 1990-05-01
• Project End: 1999-06-30
• Budget Start: 1997-07-01
• Budget End: 1998-06-30
• Support Year: 7
• Fiscal Year: 1997

Institution

• Name: University of Maryland Baltimore
• Department: Biochemistry
• Type: Schools of Medicine
• DUNS #: 003255213
• City: Baltimore
• State: MD
• Country: United States
• Zip Code: 21201

Publications

Zhu, Wei-Yong; Bunni, M; Priest, D G et al. (2002) Severe folate restriction results in depletion of and alteration in the composition of the intracellular folate pool, moderate sensitization to methotrexate and trimetrexate, upregulation of endogenous DHFR activity, and overexpression of metallothionein J Exp Ther Oncol 2:264-77

Zhu, W Y; Alliegro, M A; Melera, P W (2001) The rate of folate receptor alpha (FR alpha) synthesis in folate depleted CHL cells is regulated by a translational mechanism sensitive to media folate levels, while stable overexpression of its mRNA is mediated by gene amplification and an increase in tr J Cell Biochem 81:205-19

Yang, H; Melera, P W (1994) A genetic polymorphism within the third poly(A) signal of the DHFR gene alters the polyadenylation pattern of DHFR transcripts in CHL cells. Nucleic Acids Res 22:2694-702

Hussain, A; Yang, H; Protzman, J et al. (1994) Selection for the expression of one form of Chinese hamster dihydrofolate reductase over another during growth in methotrexate. Gene 144:277-82

Yang, H; Melera, P W (1992) Application of the polymerase chain reaction to the ribonuclease protection assay. Biotechniques 13:922-7

Melera, P W (1991) Acquired versus intrinsic resistance to methotrexate: diversity of the drug-resistant phenotype in mammalian cells. Semin Cancer Biol 2:245-55