Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor raltitrexed

Peters, Godefridus J.; Triest, Baukelien van; Backus, H. H. J.; Kuiper, C. M.; Wilt, C.L. van der; Pinedo, H.M.

doi:10.1016/s0959-8049(00)00026-5

Cited by 82 publications

(62 citation statements)

References 24 publications

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“…Unlike our results (Table I), HT-29 and LoVo cells were considered after short exposure as 5-FU resistant and sensitive cells, respectively. 3,22 By analysis of cell growth, we show that 5-FU does not affect the growth of HT-29 before the 4th or 5th day of culture which contrast with LoVo (Fig. 3).…”

Section: Discussionmentioning

confidence: 86%

“…A major difficulty encountered in vivo is to compare the expression of apoptotic genes in tumors before and after treatment. In vitro, the majority of the observations of cell death have been made after short times (24 -72 hr) of exposure to high 5-FU doses, 3,21,22 and thus differ from the conditions used in long-term therapy in vivo. 23 The aim of our study was to evaluate the accuracy of apoptosis-related proteins as markers allowing a better prediction of 5-FU resistance of tumoral cells.…”

mentioning

confidence: 99%

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Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐X_L in addition to Bax and p53 status

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Poulain

Dussaulx

et al. 2002

Intl Journal of Cancer

197

145

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Defects in apoptosis have been implicated in chemoresistance of colon cancer cells. We report here the ability to resist to 5-fluorouracil-induced apoptosis of 8 colon cancer cell lines differing in p53 and bax status: p53 ؊/0 bax ؉/؉ for TC7, SW480, HT-29; p53 ؉/؉ bax ؊/؊ for LS174T, LoVo; p53 ؉/؉ bax ؉/؊ for HCT116; p53 ؉/؉ or p53 ؉/0 bax ؉/؉ for LS513 or HCT-EB, respectively. To approximate to the in vivo therapy, the cell lines were exposed to a long-term treatment of 5-FU. The analysis of proteins implicated in the apoptotic pathway has shown that the independent analysis of p53 or bax status was not sufficient to predict the extent of drug-resistance of all cell lines. In p53 ؉/؉ cell lines but not in p53 ؊/0 cell lines, a low level of the pro-apoptotic Bax protein was correlated with a greater resistance of cells to 5-FU. In addition, we found that high levels of anti-apoptotic Bcl-2 and Bcl-x L proteins combined with a low level of Bax were correlated to high 5-FU resistance of wild-type p53 cell lines. The same correlation was obtained for 2 out of 3 mutated p53 cell lines. In conclusion, the relative levels of Bcl-2, Bcl-x L and Bax may altogether contribute to determine the resistance of a majority of colon tumor cells to long-term 5-FU treatment, whatever their p53 status.

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐X_L in addition to Bax and p53 status

Violette

Poulain

Dussaulx

et al. 2002

Intl Journal of Cancer

197

145

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“…However, the TS induction after drug exposure has not been documented in gastric cancer patients undergoing fluoropyrimidine-based chemotherapy (Uchida et al, 2001). A similar discrepancy between in vitro and in vivo systems has found in colorectal cancer (Peters et al, 2000;Uchida et al, 2001;Kamoshida et al, 2003b).…”

Section: Discussionmentioning

confidence: 98%

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

et al. 2007

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High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (Po0.01 and Po0.05, respectively). The TS-and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (Po0.0001 and Po0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy.

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“…181 Interestingly, there is an increasing evidence of interactions between TS and p53. P53 gene mutation and protein overexpression are associated with increased TS mRNA levels and TS cytoplasmatic protein in colorectal tumours, 124,128,182 It has been demonstrated that wild-type p53 is able to bind TS mRNA, which results in a feedback regulation of TS protein synthesis. 183 In cells with mutated p53, this feedback mechanism fails and, as previously mentioned, overexpression of TS is associated with poor clinical outcome.…”

Section: Jg Maring Et Almentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor raltitrexed

Cited by 82 publications

References 24 publications

Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐X_L in addition to Bax and p53 status

Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐X_L in addition to Bax and p53 status

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

Genetic factors influencing Pyrimidine-antagonist chemotherapy

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Molecular downstream events and induction of thymidylate synthase in mutant and wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the thymidylate synthase inhibitor raltitrexed

Cited by 82 publications

References 24 publications

Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐XL in addition to Bax and p53 status

Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐XL in addition to Bax and p53 status

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

Genetic factors influencing Pyrimidine-antagonist chemotherapy

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Product

Resources

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Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐X_L in addition to Bax and p53 status

Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐X_L in addition to Bax and p53 status