Evidence against a direct cytotoxic effect of alpha interferon and zidovudine in HTLV-I associated adult T cell leukemia/lymphoma

Abstract

The combination of the anti-viral agents, zidovudine (AZT) and interferon-␣ (IFN), is a potent treatment of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). In this study we investigate the possible mechanism of action of this combination by examining several cellular parameters including cell proliferation, cell cycle distribution and apoptosis. The ATL-derived T cell lines HuT-102 and MT-2 served as models. HTLV-I negative T cell lines (CEM and Jurkat) were used as controls. No significant modification of cell growth was observed except at suprapharmacological doses of AZT and IFN. Moreover, these effects were less pronounced in HTLV-I-infected cell lines compared to control cell lines. AZT and IFN treatment did not induce any significant modification of the expression of bcl-2 and p53. Interestingly no in vitro cytotoxic effect of AZT/IFN combination was observed on fresh leukemic cells derived from an acute ATL patient at diagnosis despite achievement of in vivo complete remission using the same therapy. These results suggest that the therapeutic effect of AZT and IFN is not through a direct cytotoxic effect of these drugs on the leukemic cells. Leukemia (2000) 14, 716-721.

Treatment of Adult T-cell Leukemia

“…70 For example, in patients with HTLV-1-associated myelopathy (HAM), reduction of HTLV-1 viral DNA load was reported during treatment with the reverse transcriptase inhibitor lamivudine, 71 and HTLV-1 replication was inhibited by the nucleoside reverse-transcriptase inhibitors tenofovir, abacavir, lamivudine, zalcitabine, stavudine, zidovudine and didanosine. 72,73 Another report described the successful treatment of a patient with ATL using zidovudine, lamivudine and IFN-a.…”

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

“…The best studied exemple is another leukemia, acute T cell leukemia (ATL), where infection by a virus, HTLV-I leads to the expression of a virally encoded transactivator protein, Tax that activates a large number of cellular genes, including the NF-kB survival pathway and an IL2 autocrine loop. Arsenic will induce the death of these cells (Bazarbachi et al, 1999) and tax catabolism through the proteasome (ElSabban et al, 2000). Arrays analyses demonstrate that most of the genes rapidly down-regulated by arsenic are indeed NF-kB targets, implying that Tax degradation rapidly shuts o this network of anti-apoptotic genes and providing a plausible explanation for cell death induction (A Bazarbachi and H de The , manuscript in preparation).…”

Arsenic Trioxide Inhibits Human T Cell-Lymphotropic Virus-1-Induced Syncytiums by Down-Regulating gp46

“…As 2 O 3 show promising results in the treatment of patients with ATL in combination with interferon (IFN)-a. [3][4][5][6][7][8] Although As 2 O 3 -induced apoptosis is thought to play a major role in its observed therapeutic growth inhibitory effects in treating ATL 9,10) the effects of As 2 O 3 on HTLV-1 infection/transmission have not been reported.HTLV-1 can be distinguished from all other retroviruses on the basis of the infection process: it is transmitted almost exclusively via cell-to-cell contact and cell-to-cell fusion (also termed syncytium formation), and the free viral particle is very poorly infectious.11) The HTLV-1 envelope glycoprotein is synthesized as a 61-kDa precursor that is cleaved into cellsurface (gp46) and transmembrane (gp21) proteins 12,13) and the gp46 product is thought to play an important role as the virus attachment protein. HTLV-1 can induce syncytium formation between infected cells and certain uninfected cell types 14,15) but this process can be blocked by antibodies against the gp46 protein or against gp46-derived peptides.…”

“…As 2 O 3 show promising results in the treatment of patients with ATL in combination with interferon (IFN)-a. [3][4][5][6][7][8] Although As 2 O 3 -induced apoptosis is thought to play a major role in its observed therapeutic growth inhibitory effects in treating ATL 9,10) the effects of As 2 O 3 on HTLV-1 infection/transmission have not been reported.…”