5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients

H. H J Backus, D. F. Dukers, C. J. Van Groeningen, W. Vos, E. Bloemena, D. Wouters, J. M G H Van Riel, K. Smid, G. Giaccone, H. M. Pinedo, G. J. Peters

Research output: Contribution to journalArticle

Abstract

Background: In vitro, thymidylate synthase (TS) inhibition by 5-fluorouracil (5-FU) induces thymineless apoptosis possibly via Fas receptor-Fas ligand interactions and cell-cycle arrest. In colorectal cancer patients we evaluated whether 5-FU administration also resulted in apoptosis and cell-cycle arrest and which proteins might be involved. Patients and methods: Biopsy specimens were taken from 36 patients 2, 22 or 46 hours after administration of 500 mg/m2 5-FU, and from 12 control patients who did not receive 5-FU. In frozen tissue-sections from liver metastases immunohistochemistry was performed with antibodies directed against p53, p21, E2F2, Rb, Ki67 and TS (cell-cycle related) and bax, BCL-2, BCL-x, mcl-1, PARP, caspase-3, Fas receptor and Fas ligand (apoptosis related). Apoptosis was determined by M30 immunostaining, which recognises a cleavage product of cytokeratin 18. Results: Fas receptor expression was 50% higher (P=0.036) 46 hours after 5-FU administration compared to the control group. This was associated with a 12% increase (P <0.02) in M30 positive tumour cells and with elevation of caspase-3 and PARP expression. The expression of Ki67 and E2F2 was 30% lower after 46 hours compared to the control group, whereas TS was 56% lower after 2 hours and 32% higher again after 46 hours. No differences in the expression of the other proteins were found. Conclusions: These results suggest that 5-FU decreases proliferation status and induces apoptosis possibly via the Fas pathway. Since Fas mediated cell killing is important for cytotoxic T cells this indicates that clinical studies combining immunotherapy for activation of T cells and chemotherapy using 5-FU might be very effective.

Original languageEnglish (US)
Pages (from-to)209-216
Number of pages8
JournalAnnals of Oncology
Volume12
Issue number2
DOIs
StatePublished - 2001
Externally publishedYes

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Fluorouracil
Colorectal Neoplasms
Up-Regulation
Apoptosis
Neoplasm Metastasis
CD95 Antigens
Liver
Thymidylate Synthase
Fas Ligand Protein
Cell Cycle Checkpoints
Caspase 3
Keratin-18
T-Lymphocytes
Control Groups
Frozen Sections
Immunotherapy
Cell Cycle
Proteins
Immunohistochemistry
Biopsy

Keywords

  • 5-Fluorouracil
  • Apoptosis
  • Cell-cycle arrest
  • Colorectal cancer
  • Fas
  • Thymidylate synthase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Backus, H. H. J., Dukers, D. F., Van Groeningen, C. J., Vos, W., Bloemena, E., Wouters, D., ... Peters, G. J. (2001). 5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients. Annals of Oncology, 12(2), 209-216. https://doi.org/10.1023/A:1008331525368

5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients. / Backus, H. H J; Dukers, D. F.; Van Groeningen, C. J.; Vos, W.; Bloemena, E.; Wouters, D.; Van Riel, J. M G H; Smid, K.; Giaccone, G.; Pinedo, H. M.; Peters, G. J.

In: Annals of Oncology, Vol. 12, No. 2, 2001, p. 209-216.

Research output: Contribution to journalArticle

Backus, HHJ, Dukers, DF, Van Groeningen, CJ, Vos, W, Bloemena, E, Wouters, D, Van Riel, JMGH, Smid, K, Giaccone, G, Pinedo, HM & Peters, GJ 2001, '5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients', Annals of Oncology, vol. 12, no. 2, pp. 209-216. https://doi.org/10.1023/A:1008331525368
Backus, H. H J ; Dukers, D. F. ; Van Groeningen, C. J. ; Vos, W. ; Bloemena, E. ; Wouters, D. ; Van Riel, J. M G H ; Smid, K. ; Giaccone, G. ; Pinedo, H. M. ; Peters, G. J. / 5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients. In: Annals of Oncology. 2001 ; Vol. 12, No. 2. pp. 209-216.
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abstract = "Background: In vitro, thymidylate synthase (TS) inhibition by 5-fluorouracil (5-FU) induces thymineless apoptosis possibly via Fas receptor-Fas ligand interactions and cell-cycle arrest. In colorectal cancer patients we evaluated whether 5-FU administration also resulted in apoptosis and cell-cycle arrest and which proteins might be involved. Patients and methods: Biopsy specimens were taken from 36 patients 2, 22 or 46 hours after administration of 500 mg/m2 5-FU, and from 12 control patients who did not receive 5-FU. In frozen tissue-sections from liver metastases immunohistochemistry was performed with antibodies directed against p53, p21, E2F2, Rb, Ki67 and TS (cell-cycle related) and bax, BCL-2, BCL-x, mcl-1, PARP, caspase-3, Fas receptor and Fas ligand (apoptosis related). Apoptosis was determined by M30 immunostaining, which recognises a cleavage product of cytokeratin 18. Results: Fas receptor expression was 50{\%} higher (P=0.036) 46 hours after 5-FU administration compared to the control group. This was associated with a 12{\%} increase (P <0.02) in M30 positive tumour cells and with elevation of caspase-3 and PARP expression. The expression of Ki67 and E2F2 was 30{\%} lower after 46 hours compared to the control group, whereas TS was 56{\%} lower after 2 hours and 32{\%} higher again after 46 hours. No differences in the expression of the other proteins were found. Conclusions: These results suggest that 5-FU decreases proliferation status and induces apoptosis possibly via the Fas pathway. Since Fas mediated cell killing is important for cytotoxic T cells this indicates that clinical studies combining immunotherapy for activation of T cells and chemotherapy using 5-FU might be very effective.",
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T1 - 5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients

AU - Backus, H. H J

AU - Dukers, D. F.

AU - Van Groeningen, C. J.

AU - Vos, W.

AU - Bloemena, E.

AU - Wouters, D.

AU - Van Riel, J. M G H

AU - Smid, K.

AU - Giaccone, G.

AU - Pinedo, H. M.

AU - Peters, G. J.

PY - 2001

Y1 - 2001

N2 - Background: In vitro, thymidylate synthase (TS) inhibition by 5-fluorouracil (5-FU) induces thymineless apoptosis possibly via Fas receptor-Fas ligand interactions and cell-cycle arrest. In colorectal cancer patients we evaluated whether 5-FU administration also resulted in apoptosis and cell-cycle arrest and which proteins might be involved. Patients and methods: Biopsy specimens were taken from 36 patients 2, 22 or 46 hours after administration of 500 mg/m2 5-FU, and from 12 control patients who did not receive 5-FU. In frozen tissue-sections from liver metastases immunohistochemistry was performed with antibodies directed against p53, p21, E2F2, Rb, Ki67 and TS (cell-cycle related) and bax, BCL-2, BCL-x, mcl-1, PARP, caspase-3, Fas receptor and Fas ligand (apoptosis related). Apoptosis was determined by M30 immunostaining, which recognises a cleavage product of cytokeratin 18. Results: Fas receptor expression was 50% higher (P=0.036) 46 hours after 5-FU administration compared to the control group. This was associated with a 12% increase (P <0.02) in M30 positive tumour cells and with elevation of caspase-3 and PARP expression. The expression of Ki67 and E2F2 was 30% lower after 46 hours compared to the control group, whereas TS was 56% lower after 2 hours and 32% higher again after 46 hours. No differences in the expression of the other proteins were found. Conclusions: These results suggest that 5-FU decreases proliferation status and induces apoptosis possibly via the Fas pathway. Since Fas mediated cell killing is important for cytotoxic T cells this indicates that clinical studies combining immunotherapy for activation of T cells and chemotherapy using 5-FU might be very effective.

AB - Background: In vitro, thymidylate synthase (TS) inhibition by 5-fluorouracil (5-FU) induces thymineless apoptosis possibly via Fas receptor-Fas ligand interactions and cell-cycle arrest. In colorectal cancer patients we evaluated whether 5-FU administration also resulted in apoptosis and cell-cycle arrest and which proteins might be involved. Patients and methods: Biopsy specimens were taken from 36 patients 2, 22 or 46 hours after administration of 500 mg/m2 5-FU, and from 12 control patients who did not receive 5-FU. In frozen tissue-sections from liver metastases immunohistochemistry was performed with antibodies directed against p53, p21, E2F2, Rb, Ki67 and TS (cell-cycle related) and bax, BCL-2, BCL-x, mcl-1, PARP, caspase-3, Fas receptor and Fas ligand (apoptosis related). Apoptosis was determined by M30 immunostaining, which recognises a cleavage product of cytokeratin 18. Results: Fas receptor expression was 50% higher (P=0.036) 46 hours after 5-FU administration compared to the control group. This was associated with a 12% increase (P <0.02) in M30 positive tumour cells and with elevation of caspase-3 and PARP expression. The expression of Ki67 and E2F2 was 30% lower after 46 hours compared to the control group, whereas TS was 56% lower after 2 hours and 32% higher again after 46 hours. No differences in the expression of the other proteins were found. Conclusions: These results suggest that 5-FU decreases proliferation status and induces apoptosis possibly via the Fas pathway. Since Fas mediated cell killing is important for cytotoxic T cells this indicates that clinical studies combining immunotherapy for activation of T cells and chemotherapy using 5-FU might be very effective.

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KW - Thymidylate synthase

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