Effective treatment of murine leukemia with antisense poly-2'O-(2,4-dinitrophenyl)-oligoribonucleotides.
Two antisense poly-2'-O-(2,4-dinitrophenyl)-oligoribonucleotides (poly-DNP-RNA) have been synthesized and tested for the treatment of murine leukemia. Compound I was designed as a bifunctional inhibitor of either the reverse transcriptase (RT) activity or viral envelope synthesis in Moloney murine leukemia virus (MMLV). Compound II was designed as a trifunctional inhibitor of either RT activity or envelope synthesis or protease synthesis in MMLV. Administration of either I or II to MMLV-infected mice for 3 weeks decreased viremia gradually to below the level detectable by RT-PCR. Viremia did not reappear 8 weeks after termination of treatment, when most of the mice were killed for autopsy. All infected but untreated mice died within 6 months with enlarged spleens that exhibited abnormal histologic signs and were found by PCR to contain the DNA of integrated viral genome. The infected mice that had been treated subsequently with adequate dosage of compound I or II had normal spleens, continued to live on, and had no integrated MMLV genome in their spleen and bone marrow samples. The effective i.p. dosage (ED50) for compounds I and II are 0.25 and 0.1 mg/kg, respectively, which are 200-fold to 500-fold lower than that of the monofunctional RT inhibitor poly-DNP-oligo A. The estimated effective oral dosage of compound II is 1.2 mg/kg.
Wang
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Bioenergetics Laboratory, Natural Sciences Center, State University of New York at Buffalo, 14260-3000, USA.
Wang
J H
JH
D019297:2,4-Dinitrophenol / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D010450:Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008979:Moloney murine leukemia virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012194:RNA-Directed DNA Polymerase / Q000097:blood / Q000235:genetics / Q000378:metabolism; D012192:Retroviridae Infections / Q000188:drug therapy / Q000821:virology; D018894:Reverse Transcriptase Inhibitors; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D013997:Time Factors; D014412:Tumor Virus Infections / Q000188:drug therapy / Q000821:virology; D014759:Viral Envelope Proteins / Q000096:biosynthesis / Q000235:genetics; D014766:Viremia / Q000188:drug therapy; D016662:Virus Integration / Q000187:drug effects / Q000235:genetics
D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D014759:Viral Envelope Proteins; D012194:RNA-Directed DNA Polymerase; D010450:Endopeptidases; D019297:2,4-Dinitrophenol