A survivin-responsive, conditionally replicating adenovirus induces potent cytocidal effects in adult T-cell leukemia/lymphoma.

BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Survivin-responsive, conditionally replicating adenoviruses regulated by multiple tumor-specific factors (Surv.m-CRAs), in which the expression of the adenoviral early region 1A gene is regulated by the survivin (BIRC5) promoter, can be used to treat several cancers. As survivin is overexpressed in ATL, we examined the effects of Surv.m-CRAs on ATL-selective replication and survival. METHODS: We tested two ATL cell lines and four HTLV-1-infected T-cell lines. The cells were subjected to infection with either E1-deleted, replication-defective adenoviruses or Surv.m-CRAs at various multiplicities of infection. RESULTS: Strong activation of survivin promoter was observed in all six cell lines. Moreover, the expression of the coxsackie and adenovirus receptor (CAR), which is important for adenoviral infection, was high in the cell lines. In contrast, we observed the absence of survivin promoter activity and a low expression of CAR in activated peripheral blood lymphocytes (PBLs) from healthy subjects. Surv.m-CRAs actively replicated and induced cytocidal effects in five out of six cell lines; conversely, we observed minimal viral replication and no marked cytotoxicity in normal activated PBLs. CONCLUSIONS: This is the first report demonstrating that Surv.m-CRAs constitute attractive potential anti-ATL agents.

Effects of exogenous interleukin-7 on CD8(+) T-cell survival and function in human T-cell lymphotropic virus type 1 infection.

Interleukin-7 (IL-7) mediates T-cell homeostasis through its effects on T-cell development, survival and function. In human T-cell lymphotropic virus type 1 (HTLV-1) infection, which is causally implicated in adult T-cell leukemia (ATL), the efficiency with which CD8(+) cytotoxic T-lymphocytes (CTLs) clear HTLV-1-infected cells mediates viral control and may be related to disease progression. We report here that CD127 expression in CD8(+) T-cells is independently related to disease status, and that exogenous IL-7 enhances CD8(+) T-cell survival and clearance of HTLV-1 infected cells in vitro. We conclude that CD127 down-regulation may be associated with disease status in HTLV-1 infection, and propose that exogenous IL-7 may be useful immunotherapy or cytokine adjuvant for an anti-ATL therapeutic vaccine.

Novel cytotoxic isolated from Jamaican Hyptis verticillata jacq induces apoptosis and overcomes multidrug resistance.

BACKGROUND: Adult T-cell leukemia is an aggressive hematological malignancy with a poor clinical prognosis, and a rapid resistance to chemotherapy is rapid. MATERIALS AND METHODS: Cytotoxicity assay-directed fractionation identified a novel lignan-related agent, 4-methoxy-9-(3,4,5-trimethoxyphenyl)-8, 9 - dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5H)-one (4-MTDND) from the Jamaican plant Hyptis verticillata jacq, and its effects on apoptosis, cell cycle and drug resistance were elucidated. RESULTS: The novel agent, 4-MTDND, exhibited cytotoxicity against myriad cancer types, with a wide therapeutic index of 30- to 40-fold, promoted G(2)/M arrest and up-regulated expression of pro-apoptotic proteins p53 and BAX, as well as enhanced activation of caspase-3, caspase-9 and poly (ADP ribose) polymerase, consistent with apoptosis induction. Multidrug-resistant cancer cells were as susceptible to 4-MTDND as their non-resistant control counterparts, with 4-MTDND having greater efficacy compared to standard chemotherapy agents etoposide and mitoxantrone. CONCLUSION: The novel cytotoxic agent 4-MTDND induces G(2)/M arrest and apoptosis in cancer cells possibly due to direct DNA damage or interference with topoisomerase II.