Liposomal delivery of methylphosphonate antisense oligodeoxynucleotides in chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by the presence of the Philadelphia (Ph) chromosome. Bcr-abl, the fusion gene associated with the Ph chromosome, expresses a p210bcr-abl protein that promotes a selective expansion of mature myeloid progenitor cells. Methylphosphonate (MP) oligodeoxynucleotides complementary to specific regions of the bcr-abl mRNA were incorporated in liposomes. We studied the effects of liposomal MP (L-MP) on the growth inhibition of CML-like cell lines. L-MP targeted to the breakpoint junctions of the bcr-abl mRNA inhibited the growth of CML cells. Fifty percent inhibition was achieved at approximately 1 mumol/L of L-MP oligonucleotide concentrations. The inhibitory effect was selective because growth inhibition was observed only with CML but not with control cell lines. Moreover, CML cell growth inhibition was dependent on the sequence of the MP oligodeoxynucleotides incorporated in the liposomes. The growth inhibition of CML cells by L-MP resulted from selective inhibition of the expression of the p210bcr-abl protein.
Department of Clinical Investigations, University of Texas M.D. Anderson Cancer Center, Houston 77030.
A M
AM
Tari
S D
SD
Tucker
A
A
Deisseroth
G
G
Lopez-Berestein
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D004337:Drug Carriers; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008081:Liposomes; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D009943:Organophosphorus Compounds; C032627:methylphosphonic acid; D016044:Fusion Proteins, bcr-abl