The efficacy of combined therapy of arsenic trioxide and alpha interferon in human T-cell leukemia virus type-1-infected squirrel monkeys (Saimiri sciureus)

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) has a poor prognosis owing to its intrinsic resistance to chemotherapy. Although zidovudine (AZT) and alpha interferon (IFN-alpha) give rise to some response and improve the prognosis of ATLL, alternative therapies are needed. Arsenic trioxide (AS(2)O(3)) has been shown to synergize with IFN-alpha in arresting cell growth and inducing apoptosis of ATLL cells in vitro. In this study, we evaluated the toxicity and the efficacy of this combined treatment in HTLV-I-infected squirrel monkeys (Saimiri sciureus) and HTLV-1-infected cell lines derived therefrom. We first show that treatment with As2O3 and IFN-alpha can induce growth arrest in HTLV-I-transformed monkey T-cell lines in vitro. We then show that treatment of squirrel monkeys with As2O3 in vivo is highly toxic at 0.9 or 0.3 mg/day but not at 0.14 mg/day for up to 2 weeks. Although the combination of As2O3 and IFN-alpha did not affect significantly the HTLV-1 proviral load in infected monkeys, it reduced the absolute numbers of CD3(+), CD4(+) and CD8(+) cells during treatment, with a significant reduction in the total number of circulating HTLV-1 flower cells in the infected monkeys with chronic ATLL-like disease. (c) 2006 Elsevier B.V. All rights reserved.