Acute, Multiple-Dose, and Genetic Toxicology of AR177, an Anti-HIV Oligonucleotide

AR177 (Zintevir) is a 17-mer oligonucleotide that has been shown to have anti-HIV activity and to be a potent HIV-1 integrase inhibitor in vitro, and is among the first oligonucleotides to enter human clinical trials. Acute and multiple-dose intravenous toxicity studies were performed in mice, and genetic toxicity studies were performed in vitro and in vivo in order to determine the toxicity profile of AR177. The acute toxicity study in mice showed that AR177 had an LD50 of > or = 1.5 g/kg body weight. The multipledose toxicity study in mice showed that AR177 caused male-specific mortality, and changes in serum chemistry, hematology, and histology at doses of 250 and 600 mg/kg. Clinical chemistry findings included changes in liver function, and decreased erythrocyte values at 250 and 600 mg/kg. Histopathologic findings included vacuolization of reticuloendothelial cells in phagocytic cells in lymphoid tissue, liver, lungs, heart and uterus, and extramedullary hematopoeisis in the spleen. Renal toxicity was exhibited as nephropathy and tubular necrosis in the two high-dose groups of males. A no-effect dose was not established. AR177 did not exhibit genetic toxicity in any of three mutagenic assays. In combination with previously reported toxicity studies of AR177 in monkeys, this study showed that the toxicity of AR177 is species specific.