Combination of 9-aminoacridine with Campath-1H provides effective therapy for a murine model of adult T-cell leukemia

Background: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. While much progress has been made in understanding the mechanisms of cellular dysregulation, the prognosis for aggressive ATL still remains poor. Therefore, new therapeutic approaches need to be developed. Results: Previously, we demonstrated that the viral protein Tax inactivates p53 in HTLV-1-infected T-cells. Here we show that 9-aminoacridine (9AA) through p53 reactivation and NF-kappa B inhibition has selective toxicity for infected leukemic cells independent of their p53 status. We further demonstrate that 9AA activates caspase-3/7 resulting in PARP cleavage. Next we investigated the efficacy of 9AA in the MET-1 ATL model. Alone, 9AA did not cause significant drops in surrogate tumor markers, soluble IL-2R alpha or beta 2-micorglobulin (beta 2 mu) levels with only a slight increase in survival of MET-1-bearing mice. However, in combination with Campath-1H, 9AA treatment resulted in low soluble IL-2R alpha and beta 2 mu levels at 2 and 4 weeks. Consistent with reduced tumor cell burden, combination treatment significantly increased survival of MET-1-bearing mice compared to mice treated with either drug alone. Splenic cells isolated from 9AA or combination treated mice showed increased p53 protein levels and transcriptional activity. Consistent with increased tumor suppressor activity, we found increased PARP-1 cleavage in 9AA and combination treated cells. Conclusion: Our results indicate that targeting reactivation of p53 and inhibition of NF-kappa B with acridine-derivatives in combination with other chemotherapeutics could result in increased efficacy and selective killing of tumor cells.