TOXICOLOGIC EFFECTS OF AN OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE AND ITS ANALOGS FOLLOWING INTRAVENOUS ADMINISTRATION IN RATS

The aim of the present study is to evaluate the in vivo toxicologic ef fects of a phosphorothioate oligodeoxynucleotide (PS oligo) and three of its analogs [PS oligo containing four methylphosphonate linkages at the 3' and 5'-ends (MBO 1), PS oligo containing four 2'-O-methylribon ucleosides at both the 3'- and 5'-ends (MBO 2), and PS oligo containin g an 8 bp loop region at the 3'-end (self-stabilized oligo)l. Oligodeo xynucleotides were administrated intravenously to male and female rats at doses of 3, 10, and 30 mg/kg/day for 14 days. Rats were killed on day 15, blood samples were collected for hematology and clinical chemi stry determinations, and tissues, including lymph nodes, spleens, live rs, and kidneys, were subjected to pathologic examinations. The toxici ty profiles of the four oligodeoxynucleotides were very similar, but d iffered in magnitude. In terms of the severity of the abnormalities ca used by the oligodeoxynucleotides, the order was MBO 2 > PS oligo > se lf-stabilized oligo > MBO 1. Alterations in hematology parameters incl uded thrombocytopenia, anemia, and neutropenia. Abnormalities in clini cal chemistry parameters observed with PS oligo or MBO 2 were dose-dep endent elevation of liver transaminases and reduction of the levels of alkaline phosphatase, albumin, and total protein. In addition, MBO 2 caused elevation of the total bilirubin level in male rats at the 30 m g/kg dose. No major alterations in hematology or clinical chemistry we re observed in rats receiving MBO 1 or self-stabilized oligo. Dose-dep endent enlargements of spleen, liver, and kidney were observed, especi ally in rats receiving PS oligo and MBO 2. Pathologic studies showed a generalized hyperplasia of the reticuloendothelial (RE) system in the tissues examined. Alterations in the spleen were mainly RE cell hyper plasia and hematopoietic cell proliferation. In addition to RE cell hy perplasia, lymph nodes showed necrosis, hepatocytes showed cytologic a lterations and necrosis, and kidneys showed renal tubule regeneration. The severity of pathologic changes observed was oligodeoxynucleotide dependent, in the order of MBO 2 > PS oligo > self-stabilized oligo > MBO 1.