Pharmacokinetics and in vivo effects of a six-base phosphorothioate oligodeoxynucleotide with anticancer and hematopoietic activities in swine.
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 (t1/2 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 t1/2 estimates for the three pigs were 8.96, 109, and 1.97 h (the long t1/2 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 microg/ml (0.44, 0.49, and 0.093 microM) 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 serum 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.
Mata
J E
JE
Department of Pharmacology, University of Nebraska Medical Center, Omaha 68198-6260, USA.
Jackson
J D
JD
Joshi
S S
SS
Tracewell
W G
WG
Pirruccello
S J
SJ
Murphy
B J
BJ
Bishop
M R
MR
Iversen
P L
PL
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D001774:Blood Chemical Analysis; D004586:Electrophoresis; D006410:Hematopoiesis / Q000187:drug effects*; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D013552:Swine; D013873:Thionucleotides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution; D014556:Urine / Q000737:chemistry
D000970:Antineoplastic Agents; D013873:Thionucleotides