Multi-unit ribozyme-mediated cleavage of bcr-abl mRNA in myeloid leukemias.
Chronic myelogenous leukemia is characterized by the Philadelphia chromosome, which at the molecular level results from the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9. The bcr-abl fusion gene encodes a novel tyrosine kinase with transforming activity. In this study, we have synthesized a multi-unti ribozyme that targets bcr-abl mRNA. In vitro ribozyme cleavage reactions show increased cleavage efficiency of this multi-unit ribozyme compared with single or double ribozymes. The multiunit ribozyme was then transfected into murine myeloblasts transformed with the bcr-abl gene (32D cells). Ribozyme transfection was accomplished either by liposomes or using follic acid-polylysine as a carrier. Multi-unit ribozyme transfection reduced the level of bcr-abl mRNA 3 logs when transfected via folate receptor-mediated uptake into transformed 32D cells. These results suggest that a multi-unit ribozyme could be an effective therapeutic agent for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia.
Leopold
L H
LH
Temple University Hospital, Philadelphia, PA, USA.
Shore
S K
SK
Newkirk
T A
TA
Reddy
R M
RM
Reddy
E P
EP
D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D016465:Bone Marrow Purging; D002352:Carrier Proteins / Q000378:metabolism; D002384:Catalysis; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000138:chemical synthesis / Q000235:genetics; D015195:Drug Design; D058973:Folate Receptors, GPI-Anchored; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D016372:RNA, Antisense / Q000494:pharmacology; D016337:RNA, Catalytic / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism*; D011956:Receptors, Cell Surface; D014162:Transfection
D002352:Carrier Proteins; D018076:DNA, Complementary; D058973:Folate Receptors, GPI-Anchored; D016372:RNA, Antisense; D016337:RNA, Catalytic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D016044:Fusion Proteins, bcr-abl