![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
KW Barbour, DK Hoganson, SH Berger and FG Berger
Department of Biological Sciences, University of South Carolina, Columbia 29208.
Structural changes in the macromolecular targets of pharmacological agents can result in alterations in the efficacy of these agents. In previous studies, we identified a variant structural form of thymidylate synthase (TS) that is associated with relative resistance to 5-fluoro-2'-deoxyuridine, in a human colonic tumor cell line. We now report on the use of DNA transfer techniques to examine directly the effects of each TS form on drug response. TS cDNA constructs, corresponding to the normal or variant TS mRNA, were expressed in Chinese hamster lung cells or in Escherichia coli, and response to 5- fluoro-2'-deoxyuridine was determined. We observed that expression of the variant TS, which differs from the normal form by a tyrosine to histidine substitution at residue 33, confers a 4-fold level of drug resistance in the mammalian cells, as well as in bacteria. The possible role of Tyr-33 in 5-fluoropyrimidine-mediated inhibition of TS is discussed.
This article has been cited by other articles:
|
|
 |
|
  H. Kawate, D. M. Landis, and L. A. Loeb Distribution of Mutations in Human Thymidylate Synthase Yielding Resistance to 5-Fluorodeoxyuridine J. Biol. Chem., September 20, 2002; 277(39): 36304 - 36311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Landis, C. C. Heindel, and L. A. Loeb Creation and Characterization of 5-Fluorodeoxyuridine-resistant Arg50 Loop Mutants of Human Thymidylate Synthase Cancer Res., January 1, 2001; 61(2): 666 - 672. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. E. Kitchens, A. M. Forsthoefel, K. W. Barbour, H. T. Spencer, and F. G. Berger Mechanisms of Acquired Resistance to Thymidylate Synthase Inhibitors: The Role of Enzyme Stability Mol. Pharmacol., November 1, 1999; 56(5): 1063 - 1070. [Abstract] [Full Text]
|
|
|
|
|
|
M. E. Kitchens, A. M. Forsthoefel, Z. Rafique, H. T. Spencer, and F. G. Berger Ligand-mediated Induction of Thymidylate Synthase Occurs by Enzyme Stabilization. IMPLICATIONS FOR AUTOREGULATION OF TRANSLATION J. Biol. Chem., April 30, 1999; 274(18): 12544 - 12547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Landis and L. A. Loeb Random Sequence Mutagenesis and Resistance to 5-Fluorouridine in Human Thymidylate Synthases J. Biol. Chem., October 2, 1998; 273(40): 25809 - 25817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tong, X. Liu-Chen, E. A. Ercikan-Abali, G. M. Capiaux, S.-C. Zhao, D. Banerjee, and J. R. Bertino Isolation and Characterization of Thymitaq (AG337) and 5-Fluoro-2-deoxyuridylate-resistant Mutants of Human Thymidylate Synthase from Ethyl Methanesulfonate-exposed Human Sarcoma HT1080 Cells J. Biol. Chem., May 8, 1998; 273(19): 11611 - 11618. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
