Increase of therapeutic effects by treating melanoma with targeted combinations of c-myc antisense and doxorubicin.
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.
Pastorino
Fabio
F
Differentiation Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, 16148-Genoa, Italy. fabiopastorino@ospedale-gaslini.ge.it
Mumbengegwi
Davis R
DR
Ribatti
Domenico
D
Ponzoni
Mirco
M
Allen
Theresa M
TM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D005732:Gangliosides / Q000276:immunology; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D005732:Gangliosides; D008055:Lipids; D008081:Liposomes; D020319:Oligodeoxyribonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; C019403:ganglioside, GD2; D004317:Doxorubicin