Gene expression predicts differential capecitabine metabolism, impacting on both pharmacokinetics and antitumour activity

Guichard, Sylvie; Macpherson, Janet S.; Mayer, Iain; Reid, Eilidh M.; Muir, Morwenna; Dodds, Michael; Alexander, Susan; Jodrell, Duncan I.

doi:10.1016/j.ejca.2007.10.023

Cited by 13 publications

(17 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, individualized chemotherapy based on the gene expression profiles of the individual's own cancer tissues would be a helpful strategy for selecting those patients that are likely to respond to treatment (20,33). Many studies of the mechanisms of GEM and 5-FU metabolism have suggested that certain genes/proteins are associated with sensitivity to these drugs (12)(13)(14)(15)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)39,40). However, to our knowledge, there is no study evaluating acquired cross-resistance between GEM and 5-FU and its correlation with gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…It is metabolized in the liver and tumor tissues to 5'-deoxy-5-fluorouridine (5'-DFUR) by CDA. 5'-DFUR is then converted to 5-FU by TP (26,46). Because TP is highly expressed in tumor tissues relative to host cells, capecitabine can be selectively activated in tumor tissues, suggesting that TP may contribute to capecitabine sensitivity (26,31).…”

Section: Discussionmentioning

confidence: 99%

“…Capecitabine is metabolized to 5-FU via a three-step enzymatic process, the final step being catalyzed by thymidine phosphorylase (TP) (26). Meanwhile, a late phase II study using S-1 to treat metastatic pancreatic cancer showed promising results, with a 37.5% response rate and a median OS of 9.2 months (27).…”

Section: Introductionmentioning

confidence: 99%

“…Finally, in both agents, 5-FU interacts with its pharmacological target, thymidylate synthase (TS) and inhibits DNA synthesis and repair. Increasing evidence suggests that the expression levels of TP, DPD, OPRT and TS (along with the genes that encode them) predict sensitivity to 5-FU or its prodrugs (26,(29)(30)(31)(32). Although GEM and 5-FU prodrugs are effective against advanced pancreatic cancer when used as single agents, there is a substantial subset of patients in whom the efficacy is limited or inadequate.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil

et al. 2011

View full text Add to dashboard Cite

Abstract. Gemcitabine (GEM) is the standard treatment for advanced/metastatic pancreatic cancer. However, there is a substantial subset of patients in whom the efficacy of GEM, when used as a single agent, is inadequate. Recently, the 5-fluorouracil (5-FU) prodrugs capecitabine and S-1 have been used as an alternative, either alone or in combination with GEM. The aim of the present study was to investigate the expression pattern of genes that render pancreatic cancer cells sensitive to GEM and 5-FU, and to identify markers for individualized chemotherapy, even in patients who have developed resistance. We investigated the correlation between the expression of genes associated with the metabolism of GEM and 5-FU, and sensitivity to these drugs in 15 human pancreatic cancer cell lines. We also established GEM-and 5-FU-resistant pancreatic cancer cell lines to investigate changes in the expression levels of these genes and the effects of one drug on cells resistant to the other. We found no correlation between pancreatic cancer cell sensitivity to either GEM-or 5-FU. GEM-resistant cells did not become resistant to 5-FU and vice versa. High expression of RRM1 (P=0.048) and TS x DPD (P= 0.035) correlated significantly with sensitivity to GEM and 5-FU, respectively. 5-FU-resistant cells expressed significantly higher levels of TP than parental cells (P<0.05). In conclusion, pancreatic cancer cells showed no crossresistance to GEM and 5-FU. Quantitative analyses of RRM1, TP, DPD and TS mRNA levels in pancreatic cancer cells may be useful for predicting their sensitivity to GEM and 5-FU.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The pharmacokinetics of CCB and its metabolites have been evaluated extensively in patients [21,22,23,24], but from 500 to 2500 mg/m²/d only. Over this range, the pharmacokinetics of CCB and its metabolite, 5'-DFCR were dose proportional and did not change over time.…”

Section: Discussionmentioning

confidence: 99%

Plasma disposition of capecitabine and its metabolites 5′DFCR and 5′DFUR in a standard and dose-intensified monotherapy regimen

Czejka

Schueller

Farkouh

et al. 2010

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

show abstract

Choice of Capping Group in Tripeptide Hydrogels Influences Viability in the Three‐Dimensional Cell Culture of Tumor Spheroids

et al. 2016

View full text Add to dashboard Cite

Two peptide‐derived low‐molecular‐weight gelators bearing different capping groups, 9‐fluorenylmethyloxycarbonyl (Fmoc) and phenothiazine, were synthesized and their gel networks were characterized. The variation of the N‐terminal capping group affects the viability of these hydrogels as a three‐dimensional cell culture for multicellular tumor spheroids. These results indicate that the phenothiazine capping group is a more biocompatible alternative to the widely used Fmoc moiety.

show abstract

Gene expression predicts differential capecitabine metabolism, impacting on both pharmacokinetics and antitumour activity

Cited by 13 publications

References 25 publications

Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil

Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil

Plasma disposition of capecitabine and its metabolites 5′DFCR and 5′DFUR in a standard and dose-intensified monotherapy regimen

Choice of Capping Group in Tripeptide Hydrogels Influences Viability in the Three‐Dimensional Cell Culture of Tumor Spheroids

Contact Info

Product

Resources

About