Journal
EUROPEAN JOURNAL OF CANCER
Volume 38, Issue 5, Pages 718-727Publisher
ELSEVIER SCI LTD
DOI: 10.1016/S0959-8049(01)00430-0
Keywords
quiescent cell; p53 status; apoptosis; micronucleus; hypoxic fraction; gamma-rays; radiosensitivity; BrdU
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Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mTP53) or with a neo vector as a control (SAS/neo) were inoculated subcutaneously (s.c.) into both hind legs of Balb/cA nude mice. Mice bearing tumours received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumours. The mice then received gamma-ray irradiation. Another group of mice received a series of test doses of gamma-rays while alive or after tumour clamping to obtain hypoxic fractions (HFs) in the tumours. Right after irradiation, the tumour cells were isolated and incubated with a cytokinesis blocker. The micronucleus (MN) frequency in the cells without BrdU labelling (=quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, 6 h after irradiation, tumour cell suspensions obtained in the same manner were used for determining the frequency of apoptosis in the Q cells. The MN frequency and apoptosis frequency in total (P + Q) tumour cells were determined from the tumours that were not pretreated with BrdU. In total cell populations, SAS/mTP53 cells were more radioresistant than SAS/neo cells in clonogenic survival. Q tumour cells exhibited a significantly lower apoptosis and MN frequency, probably due to their much larger HF, than total cells. In both total and Q cell fractions, SAS/mTP53 cells were less susceptible to apoptosis and more susceptible to micronucleation than SAS/neo cells. Obviously, TP53 status had the potential to influence the radiosensitivity of not only the total cells, but also the Q cells. However, irrespective of the TP53 status, significant differences in radiosensitivity between total and Q tumour cells were consistently observed. From the viewpoint of tumour control as a whole, including intratumour Q tumour cell control, a treatment modality for enhancing the Q cell response has to be considered. (C) 2002 Elsevier Science Ltd. All rights reserved.
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