Regulation of Thymidylate Synthase in Human Colon Cancer Cells Treated with 5-Fluorouracil and Interferon-Gamma

Chu, Edward; Koeller, David M.; Johnston, P. G.; Zinn, S A; Allegra, C J

doi:10.1007/978-1-4615-2488-5_16

Cited by 92 publications

(92 citation statements)

References 19 publications

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“…Other authors have pointed out an effect of Oxa on TS with a smaller FU-induced TSmRNA increase when Oxa is added to Fu (Plasencia et al, 2001). In contrast, the present data did not show that the presence of Oxa modified the FU-induced TS protein increase which had been previously described by Chu et al (1993).…”

Section: Discussioncontrasting

confidence: 55%

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

Fischel

Formento

Ciccolini³

et al. 2002

Br J Cancer

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The combination of 5-fluorouracil-folinic acid and oxaliplatin has led to a significant improvement of chemotherapy efficacy in advanced pretreated colorectal cancer. The objective of the present study was, considering the oxaplatin-5-fluorouracil-folinic acid combination, to examine the impact of one given drug on the cellular determinants of cytotoxic activity of the other drug. These cellular factors were analysed on the human colon cancer cell line WiDr in clinically relevant conditions of drug exposure ('De Gramont' schedule) with oxaliplatin-folinic acid during 2 h followed by 5-fluorouracil 48 h. The DNA binding of oxaliplatin was significantly reduced by the presence of 5-fluorouracil but this effect was time-dependent and after 50 h the platinum incorporated into DNA was identical in controls and in the drug combination. In the presence of oxaliplatin, there was less formation of FUH 2 which is the first catabolite produced in the cascade of 5-fluorouracil metabolic degradation. The effects of drugs on cell cycle were quite different from one drug to the other with oxaliplatin inducing a shift towards G 2 accumulation and 5-fluorouracil-folinic acid to a greater proportion of cells in G 1 -S. When oxaliplatin and 5-fluorouracil-folinic acid were combined the cell cycle effects were very similar to that of the 5-fluorouracil-folinic acid sequence alone. Oxaliplatin was able to reduce thymidylate synthase activity with a marked impact 28 h after the beginning of cell exposure to the drug. The 5-fluorouracil-folinic acid drug sequence led to a profound reduction in thymidylate synthase activity and this decrease was not markedly enhanced by the presence of oxaliplatin. Regarding apoptosis, changes in mitochondrial membrane permeability were observed in the presence of the tested drugs and the impact of 5-fluorouracil-folinic acid was greater than that of oxaliplatin. The addition of oxaliplatin did not amplify the action of 5-fluorouracil-folinic acid upon mitochondrial membrane permeability change. The presence of oxaliplatin itself did not modify the intracellular concentration of total reduced folates. The fact that oxaliplatin may reduce 5-fluorouracil catabolism could be central in explaining the supra-additive interaction between these drugs.

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Section: Discussioncontrasting

confidence: 55%

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

Fischel

Formento

Ciccolini³

et al. 2002

Br J Cancer

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“…In vitro studies of human colon cancer cell lines showed induction of TS protein expression after short-term exposure (8-36 hours) to 5-FU (24). Notably, in that study, there was no associated change in TS mRNA expression.…”

mentioning

confidence: 70%

“…However, changes in TS protein levels in response to antifolate treatment in cell cultures have been described. Chu et al (24) conducted experiments with human colon cancer cell lines and described an acute derepression of TS protein synthesis after short-term (8-36 hours) 5-FU exposure that did not result from increased TS mRNA. TS mRNA translation is known to be inhibited by its protein product through direct binding as part of an autoregulatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

A Phase II Trial of Pemetrexed in Advanced Breast Cancer: Clinical Response and Association with Molecular Target Expression

Gómez

Santillana

Vallejos

et al. 2006

Clinical Cancer Research

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Purpose: This phase II trial of pemetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression. Experimental Design: Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m 2 (10-minute i.v. infusion) on day 1 of a 21-day cycle, with folic acid and vitamin B 12 supplementation. Tumors were surgically removed after the last cycle of pemetrexed as clinically indicated. Biopsies were taken at baseline, 24 hours after infusion in cycle 1, and after cycle 3. Results: Sixty-one women (median age, 46 years; range, 32-72 years) were treated and were evaluable for response. Objective response rate was 31%. Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase (TS) and pemetrexed response (P = 0.103). Based on threshold analysis, patients with ''low'' baseline TS (V71) were more likely to respond to pemetrexed than patients with ''high'' baseline TS (>71). Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant (P > 0.311). TS expression increased significantly between baseline and biopsy 2 (P = 0.004) and dropped to near baseline levels at biopsy 3. Conversely, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pemetrexed chemotherapy. Conclusions: Our results suggest a potential association between ''low''pretreatmentTS expression levels and response to pemetrexed chemotherapy. Future trials examining expression levels of other genes important to the folate pathway and/or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate.

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“…These results suggest that TS expression in cancer tissues and non-neoplastic mucosa may be unchanged after 5-FU-based chemotherapy; namely, no enzyme induction occurred. Several investigators have described an acute increase of TS protein levels in the time-and dose-dependent manner after the exposure of colonic ANNALS OF Cancer Research and Therapy cancer cells to 5-FU (Backus, Dukers et al, 2001, Chu, Koeller et al, 1993. In contrast, it has been demonstrated that preoperative chemotherapy using the 5-FU derivative, UFT, induces suppression of TS activities in colorectal cancer tissues (Sakamoto, Tsukada et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

IMMUNOHISTOCHEMICAL DEMONSTRATION OF THYMIDYLATE SYNTHASE (TS), p53 PROTEIN AND BCL-XL PROTEIN IN COLORECTAL CANCER WITH PREOPERATIVE PERORAL CHEMOTHERAPY

Kamoshida

Matsuoka

Matsuyama

et al. 2003

ACRT

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of apoptosis, p53 protein, selection of patients, thymidylate synthase (TS). AbstractHigh expression of thymidylate synthase (TS), p53 protein and bcl-XL protein has been suggested to be associated with chemoresistance of colorectal malignancies. The significance of TS, p53 protein and bcl-XL protein as predictive parameters of effects of 5-fluorouracil (5-FU)-based chemotherapy on colorectal cancers was evaluated.Immunoperoxidase staining of TS, p53 protein and bcl-XL protein was performed on formalin-fixed, paraffin-embedded, 1opsied and resected specimens from 37 patients with advanced colorectal cancers, preoperatively treated with 5-FU derivatives per os. When more than one third of the cancer cells were stained, the lesions were considered high for antigen expression. High TS expression in the resected tumors was seen in 23 (74%) of 31 histologic non-responders but none in six responders. TS expression in preoperative biopsies and resected specimens was concordant in 80% of cases when two or more biopsy specimens were available.The rate of high TS expression was comparable in the control non-treated group. There was no difference between chemotherapeutic effects and the expression of p53 protein or bcl-XL protein.

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Regulation of Thymidylate Synthase in Human Colon Cancer Cells Treated with 5-Fluorouracil and Interferon-Gamma

Cited by 92 publications

References 19 publications

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

A Phase II Trial of Pemetrexed in Advanced Breast Cancer: Clinical Response and Association with Molecular Target Expression

IMMUNOHISTOCHEMICAL DEMONSTRATION OF THYMIDYLATE SYNTHASE (TS), p53 PROTEIN AND BCL-XL PROTEIN IN COLORECTAL CANCER WITH PREOPERATIVE PERORAL CHEMOTHERAPY

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