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The antitumor activity of doxorubicin against drug-resistant murine carcinoma is enhanced by oral administration of a synthetic staurosporine analogue, CGP 41251.
- Source :
-
Oncology research [Oncol Res] 1995; Vol. 7 (9), pp. 453-9. - Publication Year :
- 1995
-
Abstract
- 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.
- Subjects :
- Administration, Oral
Animals
Antibiotics, Antineoplastic administration & dosage
Antibiotics, Antineoplastic metabolism
Cell Line
Doxorubicin administration & dosage
Doxorubicin metabolism
Drug Resistance, Neoplasm physiology
Drug Therapy, Combination
Enzyme Inhibitors administration & dosage
Fluorouracil pharmacology
Injections, Intravenous
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Neoplasm Metastasis
Neoplasm Transplantation pathology
Neoplasms pathology
Protein Kinases metabolism
Staurosporine administration & dosage
Staurosporine pharmacology
Tumor Cells, Cultured
Antibiotics, Antineoplastic pharmacology
Doxorubicin pharmacology
Drug Resistance, Multiple
Enzyme Inhibitors pharmacology
Neoplasms, Experimental drug therapy
Staurosporine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0965-0407
- Volume :
- 7
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Oncology research
- Publication Type :
- Academic Journal
- Accession number :
- 8835289