Evidence against a direct cytotoxic effect of alpha interferon and zidovudine in HTLV-I associated adult T cell leukemia/lymphoma (original) (raw)
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Virology Journal
Background ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy. This T-cell non-Hodgkin lymphoma, caused by the human T-cell leukemia virus type 1 (HTLV-1), is challenging to treat. There is no known treatment for ATLL as of yet. However, it is recommended to use Zidovudine and Interferon Alfa-based regimens (AZT/IFN), chemotherapy, and stem cell transplant. This study aims to review the outcome of patients with different subtypes of ATLL treated with Zidovudine and Interferon Alfa-based regimens. Methods A systematic search was carried out for articles evaluating outcomes of ATLL treatment by AZT/IFN agents on human subjects from January 1, 2004, until July 1, 2022. Researchers assessed all studies regarding the topic, followed by extracting the data. A random-effects model was used in the meta-analyses. Results We obtained fifteen articles on the AZT/IFN treatment of 1101 ATLL patients. The response rate of the AZT/IFN regimen yielded an OR of 67% [95% ...
Journal of general …, 1997
The effect of 3h-azido-3h-deoxythymidine (AZT) on in vitro infection of peripheral blood mononuclear cells (PBMCs) isolated from normal adult individuals with human T cell leukaemia/lymphoma virus type I (HTLV-I) was evaluated. Different PBMC samples were exposed to HTLV-I by cocultivation with MT-2 (a chronically infected cell line) in the presence of 20 U/ml of human recombinant interleukin 2 (IL-2) and graded concentrations of AZT. Control and drug-treated cultures, of both infected and uninfected PBMCs, were then grown for several weeks and monitored for virological and immunological parameters. The results showed a concentrationdependent anti-proliferative effect of AZT in both infected and non-infected cultures. Production of both proviral DNA and viral RNA was inhibited not
Treatment of adult T-cell leukaemia/lymphoma: current strategy and future perspectives
Virus Research, 2001
Human T-cell leukaemia virus type I (HTLV-I) associated adult T-cell leukaemia/lymphoma (ATL) carries a very poor prognosis due to an intrinsic resistance of leukaemic cells to conventional or even high doses of chemotherapy and to an associated severe immunosuppression. Therefore, the potential role of conventional chemotherapy, high dose chemotherapy with autologous or allogeneic bone marrow transplantation remains to be defined. Important progress was achieved in the treatment of ATL with the combination of zidovudine (AZT) and interferon-alpha (IFN) which produces a high response rate in ATL patients with minimal side effects. This treatment seems to prolong the survival of patients much more than intensive chemotherapy. The success of this potentially anti-retroviral approach in the treatment of ATL suggests the existence of continuous HTLV-I replication in vivo. These encouraging results may be improved by the use of higher doses of AZT and IFN combined with other anti-retroviral agents. However, since cure seems still elusive, new therapeutic approaches or new combinations are required. For example, biological mediators such as retinoid acid, which induces apoptosis of ATL cells in vitro, may reduce drug resistance and stimulates immunity to restore anti-tumour activity against ATL cells. Alternatively, immunotherapy with anti-interleukin-2 receptor monoclonal antibodies or injection of cytotoxic T-cells directed against virus antigens could be interesting approaches which may merit further investigations in the near future. Finally, the recent demonstration that the combination of arsenic trioxide (As) and IFN induces a specific degradation of the viral transactivator Tax followed by cell cycle arrest and apoptosis of HTLV-I positive cells may constitute a valuable addition to ATL treatment.
Cell Death Discovery
Adult T cell leukemia/lymphoma (ATL) can be susceptible, at least transiently, to treatments with azidothymidine (AZT) plus IFNα and/or arsenic trioxide. However, the real role of AZT in this effect is still unclear. In fact, while reverse transcriptase (RT) inhibition could explain reduction of clonal expansion and of renewal of HTLV-1 infected cells during ATL progression, this effect alone seems insufficient to justify the evident and prompt decrease of the pro-viral load in treated patients. We have previously demonstrated that AZT is endowed with an intrinsic pro-apoptotic potential towards both peripheral blood mononuclear cells from healthy donors or some tumor cell lines, but this cytotoxic potential cannot be fully achieved unless IκBα phosphorylation is inhibited. Since the constitutive activation of NF-kappa B (NF-κB) appears a common biological basis of HTLV-1-infected cells, a pharmacological inhibition of IκBα phosphorylation seems a potential strategy for treating and...
Treatment of Adult T-Cell Leukemia-Lymphoma with Zidovudine and Interferon Alfa
N Engl J Med, 1995
Allogeneic bone marrow and peripheral blood stem cell transplantations are curative treatment modalities for adult T cell leukemia/lymphoma (ATLL) because of the intrinsic graft-versus-ATLL effect. However, limited information is available regarding whether cord blood transplantation (CBT) induces a curative graft-versus-ATLL effect against aggressive ATLL. To evaluate the effect of CBT against ATLL, we retrospectively analyzed data from 175 patients with ATLL who initially underwent single-unit CBT. The 2-year overall survival (OS) rate was 20.6% (95% confidence interval [CI], 13.8% to 27.4%). A multivariate analysis revealed that the development of graft-versus-host disease (GVHD) was a favorable prognostic factor for OS (hazard ratio, .10; 95% CI, .01 to .94; P ¼ .044). Furthermore, the 2-year OS (42.7%; 95% CI, 28.1% to 56.6%) of patients with grade 1 to 2 acute GVHD was higher than that of patients without acute GVHD (24.2%; 95% CI, 11.2% to 39.8%; P ¼ .048). However, the cumulative incidence of treatment-related mortality (TRM) was high (46.1%; 95% CI, 38.2% to 53.7%), and early death was particularly problematic. In conclusion, CBT cures patients with ATLL partly through a graft-versus-ATLL effect. However, novel interventions will be required, particularly in the early phase, to reduce TRM and optimize GVHD.
Blood, 2009
Adult T-cell leukemia/lymphoma (ATL) is resistant to chemotherapy and carries a dismal prognosis particularly for the acute and lymphoma subtypes. Promising results were obtained with the combination of zidovudine and interferon-alpha. Chronic ATL has a relatively better outcome, but poor long-term survival is noted when patients are managed with a watchful-waiting policy or with chemotherapy. In ATL cell lines, arsenic trioxide shuts off constitutive NF-κB activation and potentiates interferon-alpha apoptotic effects through proteasomal degradation of Tax. Clinically, arsenic/interferon therapy exhibits some efficacy in refractory aggressive ATL patients. These results prompted us to investigate the efficacy and safety of the combination of arsenic, interferon-alpha, and zidovudine in 10 newly diagnosed chronic ATL patients. An impressive 100% response rate was observed including 7 complete remissions, 2 complete remissions but with more than 5% circulating atypical lymphocytes, an...
Azidothymidine and interferon-alpha induce apoptosis in herpesvirus-associated lymphomas
Cancer research, 1999
Lymphoproliferative diseases that occur in immunocompromised patients are frequently associated with herpesviruses. These patients often fare poorly after treatment with conventional chemotherapy. We reported previously that patients with AIDS-related Burkitt's lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-alpha. We found that EBV-positive lymphoma cells derived from these patients cultured with AZT express CD95 and undergo apoptosis. AZT-mediated apoptosis was caspase dependent and occurred despite Fas receptor blockade. In contrast, EBV-negative lymphomas were resistant to AZT-induced apoptosis, as were EBV-positive lymphomas that expressed high levels of bcl-2. Primary effusion lymphoma (PEL) cell lines infected with human herpesvirus type 8 required IFN-alpha to potentiate AZT-induced apoptosis. IFN-alpha did not up-regulate CD95 in BL or PEL but did induce expression of the death receptor ligand, CD95 ligand. AZT-sensitive lymphomas also accumulated sig...