Pharmacogenomic dissection of resistance to thymidylate synthase inhibitors.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
MetadataShow full item record
AbstractChemoresistance is a major obstacle for successful cancer treatment. Gene amplification and altered expression are the main genetic mechanisms of tumor chemoresistance. Previously, only a limited number of genes were analyzed in each individual study using traditional molecular methods such as Northern and Southern blotting. In this study, the global gene expression patterns of 1176 genes in a panel of five thymidylate synthase (TS) inhibitor [raltitrexed (TDX) and 5-fluorouracil (5-FU)] resistant and sensitive parent cell lines were investigated using cDNA array technology. Only 28 of 1176 genes were altered >1.5-fold among resistant cells, with 2 genes (TS and YES1) consistently higher in the panel. TS mRNA and protein were consistently overexpressed in all drug-resistant tumor cell lines compared with the sensitive parent cell lines. Southern blot and FISH analysis demonstrated that the TS gene was amplified in 5-FU- and TDX-resistant cell lines. YES1 mRNA and protein were overexpressed in four drug-resistant tumor cell lines but were not overexpressed in the lymphoblast cell line W1L2(TDX), although the YES1 gene was highly amplified in these cells. The fact that W1L2 has high level (>10-fold) resistance to TS inhibitor in the absence of high YES1 expression leads to a conclusion that YES1 has no direct role in this drug resistance process. By narrowing the search from 1176 to 2 genes, the analysis of in vitro TDX and 5-FU resistance becomes more straightforward for confirmatory studies. These data provide encouragement that comprehensive transcript analysis will aid the quest for more enlightened therapeutics.
CitationCancer Research, 61 (14): 5505-10
PublisherAmerican Association for Cancer Research
CollectionsCancer Research Group
- Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex: thymidylate synthase dependent and independent networks.
- Authors: Wang W, McLeod HL, Cassidy J, Collie-Duguid ES
- Issue date: 2007 May
- Recent advances in the study of rTS proteins. rTS expression during growth and in response to thymidylate synthase inhibitors in human tumor cells.
- Authors: Dolnick BJ, Lu K, Yin MB, Rustum YM
- Issue date: 1997
- Induction of thymidylate synthase associated with multidrug resistance in human breast and colon cancer cell lines.
- Authors: Chu E, Drake JC, Koeller DM, Zinn S, Jamis-Dow CA, Yeh GC, Allegra CJ
- Issue date: 1991 Feb
- Resistance to tomudex (ZD1694): multifactorial in human breast and colon carcinoma cell lines.
- Authors: Drake JC, Allegra CJ, Moran RG, Johnston PG
- Issue date: 1996 May 17
- Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor raltitrexed.
- Authors: Peters GJ, van Triest B, Backus HH, Kuiper CM, van der Wilt CL, Pinedo HM
- Issue date: 2000 May