The antitumor activity of doxorubicin against drug-resistant murine carcinoma is enhanced by oral administration of a synthetic staurosporine analogue, CGP 41251.
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.
Killion
J J
JJ
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Beltran
P
P
O'Brian
C A
CA
Yoon
S S
SS
Fan
D
D
Wilson
M R
MR
Fidler
I J
IJ
D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation / Q000473:pathology; D009369:Neoplasms / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011494:Protein Kinases / Q000378:metabolism; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D004317:Doxorubicin; D011494:Protein Kinases; D019311:Staurosporine; C059539:midostaurin; D005472:Fluorouracil