Functional Inactivity and Mutations of p53 Differentially Affect Sensitivity to 5-Fluorouracil and Antifolate Inhibitors of Thymidylate Synthase (TS) by Altering TS Levels in Colorectal Cancer Cells

Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Nucleosides Nucleotides & Nucleic Acids (Impact Factor: 1.02). 07/2008; 27(6):740-5. DOI: 10.1080/15257770802145512
Source: PubMed


The role of p53 in altering TS expression and chemosensitivity was studied in colorectal cancer cells with wildtype, mutated, or functionally inactive p53. Cytotoxicity of TS inhibitors was studied by MTT, while PCR, Western blot, and activity assays assessed whether p53 status influenced TS expression. Lovo-175X2 cells showed increased resistance to TS inhibitors and significantly greater than wildtype expression and activity of TS. In contrast, Lovo-273X17 and Lovo-li were more sensitive to TS inhibitors and had reduced TS expression, due either to reduced TS mRNA or altered regulation of TS activity. Thus, functional inactivity and mutations of p53 differentially affect TS, potentially influencing response to TS inhibitor-based treatment.

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Available from: Godefridus J Peters, Jul 16, 2015
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    • "In addition, several studies showed that TS expression is significantly correlated with pemetrexed sensitivity both in a preclinical and clinical setting [22,49]. Functional inactivity and mutations of p53 were shown to differentially affect the expression and activity of TS [50], potentially influencing the response of A549 (wt p53) and CAL-27 (mt p53) cells to pemetrexed-based treatment. Nevertheless, different conclusions regarding the relationship between functional p53 status and sensitivity to pemetrexed have been obtained, possibly depending on the phenotypic/genotypic background of the model system used [29,51-53]. "
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