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Effects of p53 status and wortmannin treatment on potentially lethal damage repair, with emphasis on the response of intratumor quiescent cells.

PURPOSE
To examine the effects of p53 status and wortmannin treatment on potentially lethal damage repair, referring to the response of intratumor quiescent cells.


METHODS
Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were injected subcutaneously into both hind legs of Balb/cA nude mice. Mice bearing the tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. The mice then received gamma-rays with or without subsequent wortmannin administration. Right after or 24 h after gamma-ray irradiation alone or 24 h after wortmannin administration following irradiation, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with a cytokinesis blocker (cytochalasin-B), and the micronucleus (MN) frequency in cells without BrdU labeling [quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumor cells was determined from the tumors that were not pretreated with BrdU.


RESULTS
On the whole, larger values of MN frequency and surviving fraction were observed in SAS/mp53 cells than in SAS/neo cells, and Q cells showed lower MN frequencies than total cells. Without wortmannin, SAS/neo tumor cells, especially Q cells within SAS/neo tumors, showed large potentially lethal damage repair (PLDR) capacities, compared with total or Q tumor cells within SAS/mp53 tumors that showed little PLDR capacity. Wortmannin treatment inhibited the PLDR in SAS/neo tumors very effectively, but showed no apparent effect on either total or Q tumor cells within SAS/mp53 tumors.


CONCLUSION
PLDR in vivo was thought to be a p53-dependent event whether in total or Q tumor cell populations.