The effect of UCN-01 (7-hydroxystaurosporine), a potent inhibitor of protein kinase C, on fractionated radiotherapy or daily chemotherapy of a murine fibrosarcoma.

Abstract

To investigate the effect of UCN-01 (7-hydroxystaurosporine), a potent and selective protein kinase C inhibitor, on fractionated irradiation or daily chemotherapy; cis-diamminedichloroplatinum(II) (cis-DDP) or 5-fluorouracil (5-FU) in vivo. Radiosensitivity and chemosensitivity given in combination with UCN-01 were further studied in vitro to analyze these in vivo results. For in vivo studies, single-cell suspension was prepared from fourth generation FSa-II tumors and transplanted subcutaneously into the leg of 8-10-week-old C3Hf/Sed mice. Treatments were initiated when tumors reached an average diameter of 4 mm. Tumor response was studied using tumor growth and growth delay time assays. UCN-01 was given continuously for 7 days using Alzet osmotic pump (4.0 microg/microl/h or approximately 3.2 mg/kg/day). A daily gamma-ray dose of 10 Gy each was given in air for 7 days. Cis-DDP (0.7 mg/kg/day) or 5-FU (20 mg/kg/day) was given by an i.p. injection for 7 days. For in vitro studies, an established FSa-II cell line was used and cell survival was studied by colony formation assay. UCN-01 acted synergistically with fractionated irradiation, though it was slightly radioprotective in vitro and had no effect on SLD repair. The surviving fraction of the FSa-II cells treated with both UCN-01 and cis-DDP in vitro was lower than the calculated additive effect; however, the sensitizing effect of UCN-01 was not found when combined with either of the chemotherapeutic agents in vivo. Possible causes of synergism of combined UCN-01 and fractionated radiation may be that a continuous UCN-01 treatment inhibited clonogen repopulation during the course of fractionated irradiation and accumulated cells in the G2-M phase where cells are most sensitive to irradiation. UCN-01 is a promising agent that may indirectly interact with fractionated irradiation in vivo but may not with chemotherapeutic agents.