Abstract
Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd2 [S(−)C2, N-dmpa]2 (μ-dppe)Cl2}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas.
Highlights
About 44,000 new cases of leukemia are expected in the United States in 2011
The present study investigates the effect of C7a in an Adult T-cell leukemia/lymphoma (ATLL) mouse model and the mechanism of cell death induced by C7a in human T lymphotropic virus type 1 (HTLV-1)-infected and uninfected T cell leukemia lines
We show that treatment with C7a significantly increased the survival of RV-ATL engrafted mice and that C7a induced caspase-mediated apoptosis of human transformed T-cell lines and HTLV-1 infected T cells
Summary
About 44,000 new cases of leukemia are expected in the United States in 2011. Nearly half of these will be acute leukemias, including adult T-cell leukemia/lymphoma (ATLL). Novel antitumor compounds that are cytotoxic to tumor cells in vitro must be tested in preclinical animal models to determine their availability and effectiveness in vivo. Engraftment of SCID mice with patient-derived tumor cells provides an in vivo model in which to investigate the tumorigenic potential of HTLV-1-infected human lymphocytes and cell lines. We show that treatment with C7a significantly increased the survival of RV-ATL engrafted mice and that C7a induced caspase-mediated apoptosis of human transformed T-cell lines and HTLV-1 infected T cells. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
