Encapsulation of c-myc antisense oligodeoxynucleotides in lipid particles improves antitumoral efficacy in vivo in a human melanoma line.
Phosphorothioate c-myc antisense oligodeoxynucleotides [S]ODNs (free INX-6295) were encapsulated in a new liposome formulation and the antitumor activity was compared to the unencapsulated antisense in a human melanoma xenograft. The systemic administration of INX-6295 encapsulated in stabilized antisense lipid particles (SALP INX-6295) improved plasma AUC (area under the plasma concentration-time curve) and initial half-life of free INX-6295, resulting in a significant enhancement in tumor accumulation and improvement in tumor distribution of antisense oligodeoxynucleotides. Animals treated with SALP INX-6295 exhibited a prolonged reduction of c-myc expression, reduced tumor growth and increased mice survival. When administered in combination with cisplatin (DDP), SALP INX-6295 produced a complete tumor regression in approximately 30% of treated mice, which persisted for at least 60 days following the first cycle of treatment. Finally, the median survival of mice treated with DDP/SALP INX-6295 increased by 105% compared to 84% for animals treated with the combination DDP/free INX-6295. These data indicate that the biological activity and the therapeutic efficacy of c-myc antisense therapy may be improved when these agents are administered in lipid-based delivery systems.
Leonetti
C
C
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, 00158 Rome, Italy. leonetti@ifo.it
Biroccio
A
A
Benassi
B
B
Stringaro
A
A
Stoppacciaro
A
A
Semple
S C
SC
Zupi
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D015153:Blotting, Western; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism; D008081:Liposomes / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D002945:Cisplatin