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 seque nce 5'-d(TTAGGG)3' TAG-6, has been shown to inhibit telomerase activity and have antineoplastic and hematopoietic stimulatory properties. In this stud y, three immature male domestic swine (weighing approximately 40 kg) were a dministered 200 mg/m(2) of TAG-6 by continuous intravascular infusion at ra tes of 0.48 +/- 0.07 mg/hr for 14 days to evaluate the pharmacokinetics, to xicity, and tissue distribution. There was considerable variability (both w ithin 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 estimat ion 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 sta te were 0.845, 0.933, and 0.178 mu g/ml (0.44, 0.49, and 0.093 mu M) for th e three animals. Nearly 30% of the administered dose was cleared through re nal excretion by day 7 postinfusion. The distribution of TAG-6 was primaril y to the liver and kidney, but the spleen and thyroid accumulated relativel y high concentrations of TAG-6. TAG-6 was metabolized to apparently higher molecular weight products, which were observed in the urine. The size perio dicity of these apparently higher molecular weight products was in 6-base i ntervals, 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 (CPU-GM) colony formation from BM was observed. These data suggest that TAG-6 may b e a very specific pharmacophore.