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Down-Regulation of c-MYC Antigen Expression in Lymphocytes of Eµ-c-myc Transgenic Mice Treated with Anti-c-myc DNA Methylphosphonates¹

Departments of Chemistry, Biochemistry and Molecular Biology, and Surgery, University of South Florida, Tampa, Florida 33620

² To whom requests for reprints should be addressed, at Department of Pharmacology and Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107-5541.

In transgenic mice bearing a murine immunoglobulin enhancer/c-myc fusion transgene (Eµ-myc), it was found that antisense DNA methylphosphonates targeted against c-myc mRNA inhibited production of c-MYC protein in peripheral lymphocytes. The decrease in protein was measured 3–4 h after i.v. administration of a 300-nmol dose. c-MYC was detected by immunofluorescence of fixed cells stained with an anti-c-MYC antiserum. In addition, DNA methylphosphonates did not induce acute toxicity following i.v. administration of a 300-nmol dose. An identically administered scrambled sequence oligomer did not decrease c-MYC protein or induce toxicity. Finally, recovery of DNA methylphosphonates from the blood plasma of treated mice indicated that the oligomers remained intact up to 3 h, while their concentrations decreased rapidly for the first h, then slowly decreased over the next 2 h. This is the first demonstration of sequence-specific antisense DNA methylphosphonate inhibition of gene expression in the bloodstream of an animal model.

¹ This work was supported by NIH Grant CA42960 to E. W.

³ Present address: Life Sciences, Inc., 2900 72nd Street North, St. Petersburg, FL 33710.

⁴ Present address: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 5/92. Accepted 10/ 2/92.

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