Annals of Oncology 12:209-216, 2001
© 2001 European Society for Medical Oncology
research-article |
5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients
1Departments of Medical Oncology Amsterdam. The Netherlands
2Departments of Pathology, University Hospital Vrije Universiteit Amsterdam. The Netherlands
Department of Medical Oncology University Hospital Vrije Universiteit De Boelelaan 1117 1081 HV Amsterdam The Netherlands gj.peters{at}azvu.nl
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:: 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.
apoptosis, cell-cycle arrest, colorectal cancer, Fas, 5-fluorouracil, thymidylate synthase
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