High basal level gene expression of thymidine phosphorylase (platelet- derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil

Ralf Metzger, Kathleen Danenberg, C. Gail Leichman, Dennis Salonga, Edward L. Schwartz, Scott Wadler, Heinz Josef Lenz, Susan Groshen, Lawrence Leichman, Peter V. Danenberg

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Abstract

The gene expression levels of the nucleoside cleavage enzyme/angiogenic factor thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, were measured by quantitative reverse transcription-PCR in 38 pretreatment biopsies of colorectal tumors from patients who were subsequently treated with 5-fluorouracil (5-FUra) and leucovorin (LV). The range of TP gene expression (relative mRNA levels) in those tumors nonresponsive to 5-FUra was much broader than that of the responding tumors. In contrast to in vitro studies that had shown that an increased intracellular level of TP potentiates the activity of 5-FUra by converting it to the more cytotoxic nucleoside form 5-fluoro-2'deoxyuridine, tumors with the highest basal TP expressions were nonresponders to 5-FUra/LV therapy. The mean TP mRNA level in the nonresponding tumors was 2.6-fold higher than that of the responding patients. We had shown previously that high expression of thymidylate synthase (TS), the target enzyme of 5-FUra, was also a predictor of nonresponse to 5-FUra (L. Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997). TP and TS expressions were found to be independent variables in these tumors, so that low expression levels of both TS and TP in tumors predicted a very high response rate (11 of 14) to 5- FUra/LV as well as a significantly longer survival, whereas none (0 of 24) of the patients with high expression of either TP or TS were responders.

Original languageEnglish (US)
Pages (from-to)2371-2376
Number of pages6
JournalClinical Cancer Research
Volume4
Issue number10
StatePublished - Oct 1998

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Thymidine Phosphorylase
Fluorouracil
Colorectal Neoplasms
Gene Expression
Thymidylate Synthase
Leucovorin
Neoplasms
Nucleosides
Messenger RNA
Angiogenesis Inducing Agents
Enzymes
Reverse Transcription
Biopsy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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High basal level gene expression of thymidine phosphorylase (platelet- derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. / Metzger, Ralf; Danenberg, Kathleen; Leichman, C. Gail; Salonga, Dennis; Schwartz, Edward L.; Wadler, Scott; Lenz, Heinz Josef; Groshen, Susan; Leichman, Lawrence; Danenberg, Peter V.

In: Clinical Cancer Research, Vol. 4, No. 10, 10.1998, p. 2371-2376.

Research output: Contribution to journalArticle

Metzger, R, Danenberg, K, Leichman, CG, Salonga, D, Schwartz, EL, Wadler, S, Lenz, HJ, Groshen, S, Leichman, L & Danenberg, PV 1998, 'High basal level gene expression of thymidine phosphorylase (platelet- derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil', Clinical Cancer Research, vol. 4, no. 10, pp. 2371-2376.
Metzger, Ralf ; Danenberg, Kathleen ; Leichman, C. Gail ; Salonga, Dennis ; Schwartz, Edward L. ; Wadler, Scott ; Lenz, Heinz Josef ; Groshen, Susan ; Leichman, Lawrence ; Danenberg, Peter V. / High basal level gene expression of thymidine phosphorylase (platelet- derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. In: Clinical Cancer Research. 1998 ; Vol. 4, No. 10. pp. 2371-2376.
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abstract = "The gene expression levels of the nucleoside cleavage enzyme/angiogenic factor thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, were measured by quantitative reverse transcription-PCR in 38 pretreatment biopsies of colorectal tumors from patients who were subsequently treated with 5-fluorouracil (5-FUra) and leucovorin (LV). The range of TP gene expression (relative mRNA levels) in those tumors nonresponsive to 5-FUra was much broader than that of the responding tumors. In contrast to in vitro studies that had shown that an increased intracellular level of TP potentiates the activity of 5-FUra by converting it to the more cytotoxic nucleoside form 5-fluoro-2'deoxyuridine, tumors with the highest basal TP expressions were nonresponders to 5-FUra/LV therapy. The mean TP mRNA level in the nonresponding tumors was 2.6-fold higher than that of the responding patients. We had shown previously that high expression of thymidylate synthase (TS), the target enzyme of 5-FUra, was also a predictor of nonresponse to 5-FUra (L. Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997). TP and TS expressions were found to be independent variables in these tumors, so that low expression levels of both TS and TP in tumors predicted a very high response rate (11 of 14) to 5- FUra/LV as well as a significantly longer survival, whereas none (0 of 24) of the patients with high expression of either TP or TS were responders.",
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