AN ATTEMPT TO ENHANCE CHEMOSENSITIVITY OF QUIESCENT CELL-POPULATIONS IN SOLID TUMORS BY COMBINED TREATMENT WITH NICOTINAMIDE AND CARBOGEN

cis-Diamminedichloroplatinum(II) (cisplatin) was intraperitoneally inj ected into mice bearing SCC VII or EMT6/KU tumors after tell administr ations of 5-bromo-2'-deoxyuridine (BrdU) to label all the proliferatin g tumor cells. The tumors were excised 1 h after the cisplatin injecti on, minced, and trypsinized. The tumor cell suspensions were then incu bated with cytochalasin-B (a cytokinesis blocker). The micronucleus fr equency was determined, using immunofluorescence staining for BrdU, Ce lls that were not labeled with BrdU were regarded as quiescent. The mi cronucleus frequency in the total number of tumor cells was determined in tumors that had not been pretreated with BrdU, To modify the sensi tivity to cisplatin, nicotinamide was intraperitoneally injected befor e the administration of cisplatin or mice were placed in a circulating carbogen (95% O-2, 5% CO2) chamber for 30 min after cisplatin adminis tration, In both tumor systems, the micronucleus frequency in quiescen t cells was lower than that in the total cells, Nicotinamide pretreatm ent increased the micronucleus frequency in total and in quiescent cel ls in both tumor systems, and to a higher extent in total cells, The c ombination of nicotinamide and carbogen increased the micronucleus fre quency more markedly than treatment with either nicotinamide or carbog en alone. In total cells of both tumors, the nicotinamide injection in creased the uptake of [Pt-195m]cisplatin. The combined treatment raise d the uptake more markedly than did treatment with either agent alone, In total cells of the SCC VII tumor, these increases in micronucleus frequency and the [Pt-195m]cisplatin uptake following nicotinamide or combined pretreatment were significant. In both tumors, carbogen breat hing also elevated the micronucleus frequency to some degree in total and quiescent cells and the [Pt-195m]cisplatin uptake in total cells, The combined nicotinamide and carbogen treatment was considered to be useful for sensitizing tumor cells to chemotherapy with cisplatin in v ivo.