Pharmacokinetics and in vivo effects of a six-base phosphorothioate oligodeoxynucleotide with anticancer and hematopoietic activities in swine

John E. Mata, John D. Jackson, Shantaram S. Joshi, William G. Tracewell, Samuel J. Pirruccello, Barbara J. Murphy, Michael R. Bishop, Patrick L. Iversen

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

A short phosphorothioate oligodeoxynucleotide telomere mimic with the sequence 5'-d(TTAGGG)3', TAG-6, has been shown to inhibit telomerase activity and have antineoplastic and hematopoietic stimulatory properties. In this study, three immature male domestic swine (weighing approximately 40 kg) were administered 200 mg/m2 of TAG-6 by continuous intravascular infusion at rates of 0.48 ± 0.07 mg/hr for 14 days to evaluate the pharmacokinetics, toxicity, and tissue distribution. There was considerable variability (both within each animal and across animals) observed in the pharmacokinetic data. The plasma half-life (t(1/2) appeared to be short enough that it could be assumed that steady state was attained by at least 96 h after the start of the infusion. The t(1/2) estimates for the three pigs were 8.96, 109, and 1.97 h (the long t(1/2) for pig 2 may be explained by poor parameter estimation due to the variability). The volume of distribution ranged from 9.80 to 51.8 L (0.3-1.4 L/kg), and plasma clearance estimates ranged from 0.33 to 3.46 L/h (5.5-57.7 ml/min). The average plasma concentrations at steady state were 0.845, 0.933, and 0.178 μg/ml (0.44, 0.49, and 0.093 μM) for the three animals. Nearly 30% of the administered dose was cleared through renal excretion by day 7 postinfusion. The distribution of TAG-6 was primarily to the liver and kidney, but the spleen and thyroid accumulated relatively high concentrations of TAG-6. TAG-6 was metabolized to apparently higher molecular weight products, which were observed in the urine. The size periodicity of these apparently higher molecular weight products was in 6- base intervals, which is consistent with the actions of telomerase. The infusion did not produce significant changes in scrum chemistry or circulating blood cells, but a decrease in colony-forming unit-granulocyte- monocyte (CFU-GM) colony formation from BM was observed. These data suggest that TAG-6 may be a very specific pharmacophore.

Original languageEnglish (US)
Pages (from-to)205-214
Number of pages10
JournalJournal of Hematotherapy and Stem Cell Research
Volume9
Issue number2
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Immunology
  • Hematology

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