Zidovudine-based lytic-inducing chemotherapy for Epstein–Barr virus-related lymphomas

Abstract

Treatment of Epstein–Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDSPCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT–methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT–hydroxyurea treatment resulted in dramatic responses in patients with AIDSPCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas.

Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone

“…Constitutive lytic phase kinase activity in PCNS-PTLD suggests that we may be able to replace intensive induction or chemotherapeutic regimens in future trials with antiviral therapy. At the University of Miami, Ramos and colleagues reported dramatic responses in patients with AIDS-related PCNSL treated with AZT-based treatment 21 . Furthermore, AZT induced EBV lytic gene expression (BZLF1 and BXLF/vTK) followed by apoptosis in primary EBV+ lymphoma cell lines derived from AIDS patients 21 .…”

“…At the University of Miami, Ramos and colleagues reported dramatic responses in patients with AIDS-related PCNSL treated with AZT-based treatment 21 . Furthermore, AZT induced EBV lytic gene expression (BZLF1 and BXLF/vTK) followed by apoptosis in primary EBV+ lymphoma cell lines derived from AIDS patients 21 . Likewise, we show the lytic phase protein BZLF1 and BXLF1 kinase was induced in EBV+ Akata cells using our combination steroid, rituximab and antiviral regimen.…”

“…Likewise, we show the lytic phase protein BZLF1 and BXLF1 kinase was induced in EBV+ Akata cells using our combination steroid, rituximab and antiviral regimen. Prior work has demonstrated that treatment of EBV+ cell lines with glucocorticoid or nucleoside analogues is capable of triggering activation of BZLF1 and downstream kinases 21,31,46 . Here we were able to demonstrate in two separate cell line models that combination treatment with nucleoside analogues, rituximab and dexamethasone led to maximal anti-tumor effect and lytic gene expression.…”

“…Phosphorylation of nucleoside analogs, ganciclovir (GCV) and zidovudine (AZT), occurs by these lytic phase kinases, which can then inhibit viral DNA polymerase. Antiviral therapy targeting lytic gene expression is shown to be an effective treatment in some EBV-associated neoplasms 19 with in vitro data showing the additive induction of apoptosis in EBV+ cell lines treated with AZT and GCV 20,21 . Furthermore, constitutively active lytic-phase gene expression has been demonstrated in EBV+ PCNS-PTLD and systemic PTLDs 5,22,23 , raising the potential for antiviral therapy as an effective therapeutic option.…”

Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB

“…The global result is a remarkable antiproliferative effect, leading in some instances to senescence [10,19]. Moreover, only when utilized in combination with other agents, AZT was shown to exert a higher cytotoxic activity on tumor cell lines of different origins [2,3,8,30]. Indeed, all these data show that AZT may potentially cause major DNA damage, although the capability of the drug to act as a cell death inducer by itself is limited.…”