ANTITUMOR-ACTIVITY OF THE NEW, SELECTIVE PROTEIN-KINASE-C INHIBITOR 4'-N-BENZOYL STAUROSPORINE ON MURINE AND HUMAN TUMOR-MODELS

CGP 41251 (4'-N-benzoyl staurosporine, CAS 120685-11-2) has been shown to exert increased selectivity for the inhibition of protein kinase C (PKC) activity. In the present study the effect of CGP 41251 formulat ed in gelucire as an antitumor agent was studied in various types of m uring and human tumor models. When administered at a dose of 75 mg/kg 3 times daily for 9 days, CGP 41251 prolonged the life span of the mic e bearing B16 melanoma (ILS = 36%). CGP 41251, administered orally at doses of 25-225 mg/kg once daily for 9 days, however, did not show dis tinct efficacy in four kinds of murine tumor models (B16 melanoma, col on 26, colon 38 and M5076). In s.c. inoculated human tumor xenograft m odels, CGP 41251, administered orally at a dose of 200 mg/kg once dail y for 4 weeks, showed a broad antitumor spectrum. CGP 4151 inhibited t he growth of gastric cancer (H-55), colorectal cancer (H-26), breast c ancer (H-31) and lung cancer (H-74 and LC-376) with inhibition rates o f 58-80%. In a histopathologic study, increase in central necrosis and condensed nuclei and vacuolar degeneration by the treatment of CGP 41 251. In addition, CGP 41251 decreased the number of PCNA (proliferatin g cell nuclear antigen) immunoreactive cells in human tumor cells H-55 , H-26 and H-74. These results indicate that CGP 41251 shows a broad a ntitumor spectrum against human tumors, and it is suggested that CGP 4 1251 is a promising oral antitumor agent which has a novel mechanism o f action.