EFFECTS OF BIOREDUCTIVE AGENTS, TIRAPAZAMINE AND MITOMYCIN-C, ON QUIESCENT CELL-POPULATIONS IN SOLID TUMORS, EVALUATED BY MICRONUCLEUS ASSAY

Mice bearing transplantable solid tumors received 10 intraperitoneal a dministrations of 5-bromo-2'-deoxyuridine (BrdU) to label the prolifer ating (P) tumor cells, and were then irradiated with Co-60 gamma-rays or injected with cis-diamminedichloroplatinum (II) (cisplatin), The tu mor cells were isolated and incubated with cytochalasin-B (a cytokines is blacker), The micronucleus (MN) frequency in the cells without BrdU labeling, which were regarded as quiescent (Q) cells in the tumor, wa s determined using immunofluorescence staining for BrdU. The h-IN freq uency in the total (P+Q) tumor cell population was determined from tum ors that were not pretreated with BrdU, Pretreatment with tirapazamine , a bioreductive agent, could enhance the sensitivity of tumor cells, including Q cells, to radiation more markedly than mitomycin C pretrea tment as judged from an in vivo assay immediately after irradiation. P ost-irradiation administration of tirapazamine produced a large postir radiation radiosensitizing effect on both the total and Q tumor cell p opulations in vivo. Cisplatin treatment combined with tirapazamine dem onstrated that tirapazamine also has a chemosensitizing potential for both the total and Q tumor cell populations, We confirmed that the sen sitivity of Q cell populations to radiation and chemotherapy using cis platin can be enhanced by combined treatment with tirapazamine.