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 Jay Pirruccello, Barbara J. Murphy, Michael R. Bishop, Patrick L. Iversen

Research output: Contribution to journalArticle

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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 - May 30 2000

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Oligodeoxyribonucleotides
Swine
Pharmacokinetics
Telomerase
Molecular Weight
Telomere
Periodicity
Tissue Distribution
Granulocytes
Antineoplastic Agents
Half-Life
Monocytes
Blood Cells
Thyroid Gland
Stem Cells
Spleen
Urine
Kidney
Liver

ASJC Scopus subject areas

  • Immunology
  • Hematology

Cite this

Pharmacokinetics and in vivo effects of a six-base phosphorothioate oligodeoxynucleotide with anticancer and hematopoietic activities in swine. / Mata, John E.; Jackson, John D.; Joshi, Shantaram S; Tracewell, William G.; Pirruccello, Samuel Jay; Murphy, Barbara J.; Bishop, Michael R.; Iversen, Patrick L.

In: Journal of Hematotherapy and Stem Cell Research, Vol. 9, No. 2, 30.05.2000, p. 205-214.

Research output: Contribution to journalArticle

Mata, John E. ; Jackson, John D. ; Joshi, Shantaram S ; Tracewell, William G. ; Pirruccello, Samuel Jay ; Murphy, Barbara J. ; Bishop, Michael R. ; Iversen, Patrick L. / Pharmacokinetics and in vivo effects of a six-base phosphorothioate oligodeoxynucleotide with anticancer and hematopoietic activities in swine. In: Journal of Hematotherapy and Stem Cell Research. 2000 ; Vol. 9, No. 2. pp. 205-214.
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