The Role of Thymidylate Synthase Induction in Modulating p53-regulated Gene Expression in Response to 5-Fluorouracil and Antifolates


Autoria(s): Longley, Daniel B; Boyer, John; Allen, Wendy L; Latif, Tariq; Ferguson, Paul R; Maxwell, Pamela J; McDermott, Ultan; Lynch, Maria; Harkin, D Paul; Johnston, Patrick G
Data(s)

2002

Resumo

<p>Thymidylate synthase (TS) is a critical target for chemotherapeutic agents such as 5-fluorouracil (5-FU) and antifolates such as tomudex (TDX),multitargeted antifolate, and ZD9331. Using the MCF-7 breast cancer line, we have developed p53 wild-type (M7TS90) and null (M7TS90-E6) isogenic lines with inducible TS expression (approximately 6-fold induction compared with control after 48 h). In the M7TS90 line, inducible TS expression resulted in a moderate approximately 3-fold increase in 5-FU IC-50(72 h) dose and a dramatic >20-fold increase in the IC-50(72 h) doses of TDX, multitargeted antifolate, and ZD9331. S-phase cell cycle arrest and apoptosis induced by the antifolates were abrogated by TS induction. In contrast, cell cycle arrest and apoptosis induced by 5-FU was unaffected by TS expression levels. Inactivation of p53 significantly increased resistance to 5-FU and the antifolates with IC-50(72 h) doses for 5-FU and TDX of >100 and >10 microM, respectively, in the M7TS90-E6 cell line. Furthermore, p53 inactivation completely abrogated the cell cycle arrest and apoptosis induced by 5-FU. The antifolates induced S-phase arrest in the p53 null cell line; however, the induction of apoptosis by these agents was significantly reduced compared with p53 wild-type cells. Both inducible TS expression and the addition of exogenous thymidine (10 microM) blocked p53 and p21 induction by the antifolates but not by 5-FU in the M7TS90 cell line. Similarly, inducible TS expression and exogenous thymidine abrogated antifolate but not 5-FU-mediated up-regulation of Fas/CD95 in M7TS90 cells. Our results indicate that in M7TS90 cells, inducible TS expression modulates p53 and p53 target gene expression in response to TS-targeted antifolate therapies but not to 5-FU.</p>

Identificador

https://pure.qub.ac.uk/portal/en/publications/the-role-of-thymidylate-synthase-induction-in-modulating-p53regulated-gene-expression-in-response-to-5fluorouracil-and-antifolates(b8d68873-8379-44ca-912d-5ac9b24b9932).html

http://www.scopus.com/inward/record.url?scp=0036570007&partnerID=8YFLogxK

http://cancerres.aacrjournals.org/content/62/9/2644.long

Idioma(s)

eng

Direitos

info:eu-repo/semantics/restrictedAccess

Fonte

Longley , D B , Boyer , J , Allen , W L , Latif , T , Ferguson , P R , Maxwell , P J , McDermott , U , Lynch , M , Harkin , D P & Johnston , P G 2002 , ' The Role of Thymidylate Synthase Induction in Modulating p53-regulated Gene Expression in Response to 5-Fluorouracil and Antifolates ' , Cancer Research , vol. 62 , no. 9 , pp. 2644-2649 .

Palavras-Chave #Antigens, CD95 #Breast Neoplasms #Cell Cycle #Enzyme Induction #Fluorouracil #Folic Acid Antagonists #Gene Expression Regulation, Enzymologic #Gene Expression Regulation, Neoplastic #Genes, p53 #Humans #Thymidylate Synthase #Tumor Cells, Cultured #Tumor Suppressor Protein p53 #Up-Regulation #/dk/atira/pure/subjectarea/asjc/1300/1306 #Cancer Research #/dk/atira/pure/subjectarea/asjc/2700/2730 #Oncology
Tipo

article