Inhibition of leukemia cell proliferation by receptor-mediated uptake of c-myb antisense oligodeoxynucleotides.
Exposure of human leukemia HL-60 cells to an oligodeoxynucleotide complementary to an 18-base sequence (codons 2-7) of c-myb-encoded mRNA has previously been shown to result in inhibition of cell proliferation. Because HL-60 cells express high levels of transferrin receptor we adapted a DNA delivery system based on receptor-mediated endocytosis to introduce myb oligomers complexed with a transferrin-polylysine conjugate into those cells. A DNA.RNA duplex resistant to S1 nuclease digestion was detected as early as 12 hr after culture of HL-60 cells in the presence of the myb antisense/transferrin-polylysine complex. Exposure of HL-60 cells to the myb antisense/transferrin-polylysine complex resulted in rapid and profound inhibition of proliferation and loss of cell viability much more pronounced than that occurring in cells exposed to free myb antisense oligodeoxynucleotides. The transferrin-polylysine/myb sense complex or the transferrin-polylysine conjugate alone had no effect on HL-60 cell proliferation and viability. These findings indicate that myb synthetic oligodeoxynucleotides enter efficiently into HL-60 by transferrin receptor-mediated endocytosis and exert a profound biological effect. Such a delivery system could exploit other ligand-receptor interactions for the selective delivery of oncogene-targeted antisense oligodeoxynucleotides.
Citro
G
G
Laboratorio Chemioterapia Sperimentale, Istituto Tumori Regina Elena, Rome, Italy.
Perrotti
D
D
Cucco
C
C
D'Agnano
I
I
Sacchi
A
A
Zupi
G
G
Calabretta
B
B
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004273:DNA, Neoplasm / Q000302:isolation & purification / Q000378:metabolism; D004337:Drug Carriers; D005455:Fluorescent Antibody Technique; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000378:metabolism* / Q000494:pharmacology*; D009857:Oncogenes; D011107:Polylysine / Q000138:chemical synthesis / Q000031:analogs & derivatives; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000302:isolation & purification / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism*; D014168:Transferrin / Q000138:chemical synthesis / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004337:Drug Carriers; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011990:Receptors, Transferrin; D014168:Transferrin; C072481:transferrin-polylysine conjugate; D011107:Polylysine