We evaluated the therapeutic efficacy against murine
drug-sensitive and
drug-resistant
tumor of a
combination chemotherapy regimen comprising
intravenous administration of
doxorubicin (DXR) plus
oral administration of the
staurosporine analogue
CGP 41251 (
benzoylstaurosporine), a highly specific inhibitor of
protein kinase C (PKC). In vitro studies indicated that the simultaneous presence of noncytotoxic concentrations of
CGP 41251 with DXR decreased the median inhibitory concentration (IC50) about 3-fold in the
drug-sensitive parental murine cell lines, CT-26P and UV2237. Similar treatment of
drug-resistant variants of these tumor cell lines reversed their multiple
drug resistant (MDR) phenotype (about a 5-fold increase in their sensitivity to DXR) and increased the cellular accumulation of DXR. Combination
therapy in vivo with DXR and
CGP 41251 significantly inhibited the SC growth of the
drug-resistant CT-26R500 cell line. This effect was confirmed by the ability of this combination
therapy to reduce the number of lung
metastases produced by IV injection of either the
drug-sensitive parental line CT-26P or the
drug-resistant subline, CT-26R500. PKC activity was reduced in
tumors derived from mice treated with either DXR or
CGP 41251, but not from those derived from mice treated with the combination. These results reflect one of the infrequent examples of being able to modulate the sensitivity of in vivo-grown
tumors to the antitumor effects of an MDR-related
drug and suggest a basis for evaluation of
CGP 41251 in clinical trials.