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Research ArticleArticle

Safety, Pharmacokinetics, and Tissue Distribution of Liposomal P-Ethoxy Antisense Oligonucleotides Targeted to Bcl-2

Yolanda Gutiérrez-Puente, Ana M. Tari, Clifton Stephens, Michael Rosenblum, Reyes Tamez Guerra and Gabriel Lopez-Berestein
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 865-869;
Yolanda Gutiérrez-Puente
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Ana M. Tari
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Clifton Stephens
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Michael Rosenblum
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Reyes Tamez Guerra
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Gabriel Lopez-Berestein
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Abstract

Antisense oligonucleotides (oligos) have the ability to selectively block disease-causing genes, thereby inhibiting production of disease-associated proteins. However, their effectiveness has been limited by their low intracellular delivery. We had previously demonstrated that liposomes could increase the intracellular uptake of P-ethoxy oligos, hydrophobic analogs of phosphodiesters, and that liposomal Bcl-2 P-ethoxy antisense oligos (L-Bcl-2) could selectively inhibit Bcl-2 protein production, thereby inducing growth inhibition in Follicular Lymphoma cell lines. To understand the in vivo behavior of L-Bcl-2, we conducted a series of studies to evaluate the safety, pharmacokinetics, and tissue distribution of i.v. injections of L-Bcl-2 in normal rodents. Daily administration of 20 mg of L-Bcl-2/kg of body weight in 5 consecutive days had no adverse effects on renal or hepatic functions, nor on hematological parameters. Histopathology also did not reveal any significant changes in the morphology of the organs studied. In rats, the area under the curve of L-Bcl-2 reflects a two-compartment model of distribution with a biphasic plasma clearance. TheT½α andT½β were approximately 8 min and 4.2 h, respectively, and the Vd was 79 ml, indicating a broad body distribution. The highest concentrations of L-Bcl-2 were found in spleen > liver > kidneys. These studies showed that in the schedules studied no significant toxicity associated with L-Bcl-2 was observed over 6 weeks, and that L-Bcl-2 could be widely distributed in the body.

Footnotes

  • Send reprint requests to: Dr. Gabriel Lopez-Berestein, M.D., Department of Bioimmunotherapy, The University of Texas M.D. Anderson Cancer Center, 1515 Holcom Blvd. Box 060, Houston, TX 77030. E-mail: glopez{at}utmdacc.mdacc.tmc.edu

  • ↵1 This work was funded in part by a grant from the Gabriella Rich Leukemia Fund to Gabriel Lopez-Berestein.

  • ↵2 Current address: Department of Bioimmunotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

  • ↵3 Current address: Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

  • ↵4 Current address: Departamento de Inmunologı́a y Microbiologı́a, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, Monterrey, N.L., Mexico.

  • Received for publication May 20, 1999.

  • Abbreviations:
    oligos
    oligonucleotides
    FL
    Follicular Lymphoma
    L-Bcl-2
    liposomal Bcl-2 P-ethoxy antisense oligos
    BUN
    blood urea nitrogen
    SGOT
    serum glutamic-oxaloacetic transaminase
    • Accepted August 3, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

Safety, Pharmacokinetics, and Tissue Distribution of Liposomal P-Ethoxy Antisense Oligonucleotides Targeted to Bcl-2

Yolanda Gutiérrez-Puente, Ana M. Tari, Clifton Stephens, Michael Rosenblum, Reyes Tamez Guerra and Gabriel Lopez-Berestein
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 865-869;

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Research ArticleArticle

Safety, Pharmacokinetics, and Tissue Distribution of Liposomal P-Ethoxy Antisense Oligonucleotides Targeted to Bcl-2

Yolanda Gutiérrez-Puente, Ana M. Tari, Clifton Stephens, Michael Rosenblum, Reyes Tamez Guerra and Gabriel Lopez-Berestein
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 865-869;
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