Lack of toxicity associated with the systemic administration of antisense oligonucleotides for treatment of rats bearing LNCaP prostate tumors.

Antisense oligonucleotides (oligos) are now in clinical trials for the treatment of a variety of diseases. However, concern is sometimes expressed as to the toxicity of such compounds, particularly those with phosphorothioated backbones. We have previously reported (J. Surg. Oncol. 62, 194, 1996) our experience in treating nude mice bearing human PC-3 prostate tumors with phosphorothioated antisense oligos directed against mRNA encoding transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGFR). This therapy resulted in a 75% (9/12) response rate for the intralesional treatment and a 100% (3/3) response rate for the systemic administration utilizing Alzet diffusion pumps. In the current study, athymic nude rats bearing orthotopically implanted LNCaP tumors, whose establishment was confirmed by the expression of human PSA, were implanted subcutaneously with Alzet diffusion pumps and treated systemically for 14 days with a total of 1 mg of each oligo (2 mg total). Controls consisted of five untreated rats similarly inoculated with LNCaP cells, but which did not receive antisense oligos. After 2 weeks the rats were sacrificed and serum samples were evaluated for BUN, creatinine, LDH and SGOT. Lungs, kidneys, livers, spleens and prostates were also removed for pathologic evaluation. There were no serum marker differences between groups nor was there histologic evidence of oligo toxicity seen in any evaluated tissue. Of interest was the observation that the livers and spleens, as well as prostates, of treated animals revealed mild lymphocytic infiltration compared to controls. We conclude that at this level of administration, there is no toxicity associated with 14-day oligo treatment.