Increase of therapeutic effects by treating melanoma with targeted combinations of c-myc antisense and doxorubicin.

Abstract

Patients with advanced or metastatic melanoma have a very poor prognosis, due to the resistance of melanoma cells to conventional chemotherapy. We previously reported that coated cationic liposomes targeted with a monoclonal antibody against the disialoganglioside GD(2) and containing c-myc antisense oligodeoxynucleotides (alpha GD(2)-CCL[c-myc-as]) induced partial tumor growth arrest in melanoma xenografts. Here we addressed the role of c-myc-asODN treatment in the susceptibility to doxorubicin (DXR) in human melanoma cells. Cytotoxicity studies revealed that growth of melanoma cells was inhibited to a greater extent by alpha GD(2)-CCL[c-myc-as] than by the corresponding non-targeted formulations or by free c-myc-as. Targeted c-myc-as sensitized cells to DXR, reducing the IC(50) by approximately 10-fold. Scrambled ODNs had no effect on the IC(50) of DXR. Compared to either treatment alone, combination of targeted c-myc-as and DXR resulted in earlier apoptosis and in cell death after 2 days of treatment. In vivo experiments revealed that liposomal formulations of c-myc-as and DXR, both targeted via GD(2), led to the most pronounced delay in tumor growth when administered in a sequential manner. As a result, their combination translates into a statistically significant suppression of blood vessel density and an enhanced apoptosis, compared to all treatments given separately. Our data indicate the increasing cell sensitivity to DXR by c-myc-asODNs as a promising basis for developing novel anti-tumor strategy against advanced melanoma.

• Authors: Fabio Pastorino, Davis R Mumbengegwi, Domenico Ribatti, Mirco Ponzoni, Theresa M Allen
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 126 Issue 1 Pg. 85-94 (Feb 18 2008) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 18166243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Antibodies, Monoclonal
• Drug Carriers
• Gangliosides
• Lipids
• Liposomes
• Oligodeoxyribonucleotides, Antisense
• Proto-Oncogene Proteins c-myc
• ganglioside, GD2
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, pharmacology, therapeutic use)
• Antibodies, Monoclonal (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Adhesion
• Cell Line, Tumor
• Cell Survival (drug effects)
• Doxorubicin (administration & dosage, pharmacology, therapeutic use)
• Drug Carriers (chemistry)
• Female
• Gangliosides (immunology)
• Humans
• Lipids (chemistry)
• Liposomes
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Oligodeoxyribonucleotides, Antisense (administration & dosage, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-myc (biosynthesis)