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Colorectal Tumors Responding to 5-Fluorouracil Have Low Gene Expression Levels of Dihydropyrimidine Dehydrogenase, Thymidylate Synthase, and Thymidine Phosphorylase
Ist Teil von
Clinical cancer research, 2000-04, Vol.6 (4), p.1322-1327
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2000
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
We
had previously shown that high gene expressions (mRNA levels) of
thymidylate synthase ( TS ; Leichman et
al. , J. Clin. Oncol., 15: 3223–3229, 1997)
and thymidine phosphorylase ( TP ; Metzger et
al. , Clin. Cancer Res., 4: 2371–2376, 1998) in
pretreatment tumor biopsies could identify tumors that would be
nonresponsive to 5-fluorouracil (5-FU)-based therapy. In this study, we
investigated the association between intratumoral gene expression of
the pyrimidine catabolism enzyme dihydropyrimidine dehydrogenase
( DPD ) and the response of colorectal tumors to the same
5-FU-based protocol. DPD expressions were measured by
quantitative reverse transcription-PCR in 33 pretreatment biopsies of
colorectal tumors from patients who went on to receive treatment with
5-FU and leucovorin (LV). The range of DPD gene
expression in those tumors that were nonresponsive to 5-FU was much
broader than that of the responding tumors. None of the tumors with
basal-level DPD expressions above a
DPD :β-actin ratio of 2.5 × 10 −3
(14 of 33) were responders to 5-FU/LV therapy, whereas those tumors
with DPD gene expressions below
DPD :β-actin ratio of 2.5 × 10 −3
had a response rate of 50%. There was no correlation among
DPD , TS , and TP expression
values in this set of colorectal tumors, which indicated that these
gene expressions are independent variables. All of the tumors that
responded to 5-FU therapy (11 of 33) had expression values of all three
of the genes, TS , TP , and
DPD , below their respective nonresponse cutoff values,
whereas, in each of the nonresponding tumors, at least one of these
gene expressions was high. The patients with low expression of all
three of the genes had significantly longer survival than patients with
a high value of any one of the gene expressions. The results of this
study show that intratumoral gene expression level of
DPD is associated with tumor response to 5-FU and that
the use of more than one independent determinant of response permits
the identification of a high percentage of responding patients.