Enzymatically-targeted 131I therapy for herpesvirus-associated malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3010-3010
Author(s):  
D. Fu ◽  
V. Lemas ◽  
C. Foss ◽  
J. Fox ◽  
M. Pomper ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Tumor Regression ◽  
Human Cancer ◽  
Primary Effusion Lymphoma ◽  
Nucleoside Analogs ◽  
Kaposi’S Sarcoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Barr Virus ◽  
Bortezomib Treatment

3010 Background: Epstein-Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV) are associated with tumors including AIDS-related lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma and Kaposi’s sarcoma. Both viruses encode kinases that selectively phosphorylate nucleoside analogs such as ganciclovir and FIAU. We hypothesized that it might be possible to use the viral enzymes to specifically concentrate 131I-FIAU in tumor cells harboring virus and thus deliver therapeutic radiation. Bortezomib is a potent stimulator of viral kinase expression in gammaherpesvirus tumor cell lines. Methods: We evaluated the effect of 131I-FIAU on human cancer xenografts in SCID mice. These included a tumor line engineered to constitutively express the EBV thymidine kinase (EBVTK), and a control engineered with a sham vector (SHAM), as well 2 EBV(+) Burkitt’s lymphoma (BL) lines, and 1 KSHV(+) primary effusion lymphoma (PEL) cell line. Mice were treated with buffer, bortezomib 2 ug/gm, or I-FIAU, or I-FIAU and bortezomib in combination. For imaging, mice, 125I -FIAU and SPECT were used. For therapy, 131I-FIAU was used and tumor dimensions were monitored with calipers. Results: Treatment with buffer had no effect on on 3 EBVTK tumors and 3 SHAM tumors all of which increased in volume. Treatment with 1.4 mCi 131I-FIAU alone led to tumor responses (>90% volume reduction at 10 days) in 3/3 mice with EBVTK tumors and 0/3 mice with SHAM tumors. Treatment with 131I-FIAU alone had no effect on BL (0/3) or PEL (0/9) xenografts and all tumors increased in volume. Treatment with bortezomib induced modest responses in all tumors but had no greater effect on EBVTK tumors than SHAM tumors. However, treatment with bortezomib and 131I-FIAU led to marked tumor regression (>95%) in each of the virus-associated tumors (3/3 BL, 9/9 PEL). SPECT imaging with 125I-FIAU showed selective concentration of radiolabel in tumor tissue in the EBVTK tumor (2/2) and in viral tumors (6/6) when bortezomib was administered. There was no selective concentration in the absence of bortezomib treatment in the viral tumors (0/8). Conclusions: Treatment with bortezomib leads to selective concentration of labeled FIAU in the herpesvirus-associated tumor xenografts evaluated and to regression of tumor when the isotope is 131I. No significant financial relationships to disclose.

Nelfinavir Activates Epstein-Barr Virus and Kaposi's Sarcoma Herpesvirus Lytic Cycle by Inducing ER Stress

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5011-5011
Author(s):  
Courtney Shirley ◽  
Nene Kalu ◽  
Richard F Ambinder
Keyword(s):  
Gene Expression ◽  
Er Stress ◽  
Kaposi's Sarcoma ◽  
Epstein Barr Virus ◽  
Primary Effusion Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Barr Virus ◽  
Virion Production ◽  
Epstein Barr

Abstract Abstract 5011 Epstein-Barr virus (EBV) and Kaposi's Sarcoma herpesvirus (KSHV) are associated with lymphomas and other malignancies. We previously demonstrated that the proteasome inhibitor, bortezomib, leads to ER stress, induction of the unfolded protein response (UPR), and activation of EBV lytic gene expression.1 Here we investigate nelfinavir, an HIV protease inhibitor that has been reported to induce the UPR.2 Nelfinavir treatment of EBV Burkitt's lymphoma (BL) and KSHV primary effusion lymphoma (PEL) cell lines resulted in changes indicative of ER stress: elevated levels of ATF4, XBP1(s), and CHOP10 (Figure 1), as well as the EBV and KSHV immediate early proteins ZTA and RTA (Figure 2), respectively. The appearance of these UPR markers preceded expression of viral lytic RNAs. Regulated knockdown of Bip, an ER-stress sensor and activator of the UPR, by shRNA inhibited viral lytic RNA induction. These effects were observed using drug levels at or just above the levels achieved with standard clinical dosing of nelfinavir. Gantt et al. have reported that nelfinavir inhibits herpes virion production, including KSHV, in vitro.3 The ability to activate viral gene expression in combination with inhibition of virion production may identify nelfinavir as an especially promising agent for virus-targeted cancer therapies.Figure 1Figure 1. Figure 2Figure 2. Analysis of nelfinavir (NFV) induced ER stress markers by RT-qPCR in Burkitt's lymphoma (Akata) and primary effusion lymphoma (BCBL-1) cells. Analysis of nelfinavir (NFV) induced lytic activation by RT-qPCR in Burkitt's lymphoma (Akata) and primary effusion lymphoma (BCBL-1) cells. Disclosures: No relevant conflicts of interest to declare.

Imaging and therapy for Epstein-Barr virus-associated gastric cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4644-4644
Author(s):  
D. Fu ◽  
J. Chong ◽  
C. Foss ◽  
J. Fox ◽  
S. Wang ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Tumor Regression ◽  
Human Cancer ◽  
Nucleoside Analogs ◽  
Scid Mice ◽  
Tumor Xenografts ◽  
Barr Virus ◽  
Bortezomib Treatment ◽  
Epstein Barr

4644 Background: Epstein-Barr virus (EBV) has been identified in a wide variety of malignancies, including gastric carcinomas. The virus encodes kinases that phosphorylate nucleoside analogs such as 2’-deoxy-2’-fluoro-5-iodo-1-beta-D- arabinofuranosyluracil (FIAU). We hypothesized that it might be possible to use the viral enzyme to specifically concentrate [125I]FIAU or [131I] FIAU in tumor cells harboring virus and thus deliver imaging and therapeutic radiation. Bortezomib is a potent stimulator of viral kinase expression in EBV tumor cell lines. Methods: We imaged lytic induction in vivo and evaluated the effect of [131I] FIAU on human cancer xenografts in SCID mice. These include a tumor line engineered to constitutively express the EBV thymide kinase (EBVTK), and a control engineered with a sham vector (SHAM), as well one EBV-associated human gastric tumor (KT tumor). Mice were treated with buffer, bortezomib (2μg/g), or radiolabeled FIAU or radiolabeled FIAU and bortezomib in combination. For imaging, mice, [125I]-FIAU and SPECT/CT were used. For therapy, 131I-FIAU was used and tumor dimensions were monitored with calipers. Results: SPECT/CT imaging with [125I]-FIAU of tumor-bearing SCID mice showed selective concentration of radiotracer in tumor tissue in EBVTK (3/3) and in EBV-associated KT tumors (3/3) when animals were pretreated with bortezomib. Treatment with buffer had no effect on 3 EBVTK tumors and 3 SHAM tumors all of which increased in volume. Treatment with 1.6 mCi of [131I]-FIAU alone led to tumor response in 3/3 mice with EBVTK tumors and 0/3 mice with SHAM tumors. Treatment with [131I]-FIAU alone had no effect on EBV KT tumor xenografts (0/3) and all tumors increased in volume. Treatment with bortezomib induced modest responses in all KT tumors. However, treatment with bortezomib and [131I]-FIAU led to marked tumor regression (>80%) in EBV-associated KT tumors (3/3). Conclusions: Treatment with bortezomib leads to selective concentration of radiolabeled FIAU in the EBV-associated tumor xenografts. In combination with [131I]-FIAU it leads to tumor regression. No significant financial relationships to disclose.

scholarly journals Nanotechnology Frontiers in γ-Herpesviruses Treatments

2021 ◽  
Vol 22 (21) ◽  
pp. 11407
Author(s):  
Marisa Granato
Keyword(s):  
Kaposi's Sarcoma ◽  
Cell Cycle Progression ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Castleman Disease ◽  
Etiologic Agent ◽  
Barr Virus ◽  
Associated Diseases

Epstein–Barr Virus (EBV) and Kaposi’s sarcoma associated-herpesvirus (KSHV) are γ-herpesviruses that belong to the Herpesviridae family. EBV infections are linked to the onset and progression of several diseases, such as Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC), and lymphoproliferative malignancies arising in post-transplanted patients (PTDLs). KSHV, an etiologic agent of Kaposi’s sarcoma (KS), displays primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Many therapeutics, such as bortezomib, CHOP cocktail medications, and natural compounds (e.g., quercetin or curcumin), are administrated to patients affected by γ-herpesvirus infections. These drugs induce apoptosis and autophagy, inhibiting the proliferative and cell cycle progression in these malignancies. In the last decade, many studies conducted by scientists and clinicians have indicated that nanotechnology and nanomedicine could improve the outcome of several treatments in γ-herpesvirus-associated diseases. Some drugs are entrapped in nanoparticles (NPs) expressed on the surface area of polyethylene glycol (PEG). These NPs move to specific tissues and exert their properties, releasing therapeutics in the cell target. To treat EBV- and KSHV-associated diseases, many studies have been performed in vivo and in vitro using virus-like particles (VPLs) engineered to maximize antigen and epitope presentations during immune response. NPs are designed to improve therapeutic delivery, avoiding dissolving the drugs in toxic solvents. They reduce the dose-limiting toxicity and reach specific tissue areas. Several attempts are ongoing to synthesize and produce EBV vaccines using nanosystems.

scholarly journals Molecular virology of Kaposi's sarcoma–associated herpesvirus

2001 ◽  
Vol 356 (1408) ◽  
pp. 499-516 ◽  
Author(s):  
Patrick S. Moore ◽  
Yuan Chang
Keyword(s):  
Regulatory Networks ◽  
Kaposi's Sarcoma ◽  
Fas Ligand ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Control Mechanisms ◽  
Inhibitory Protein ◽  
Barr Virus ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Kaposi's sarcoma–associated herpesvirus (KSHV), the most recently discovered human tumour virus, is the causative agent of Kaposi's sarcoma, primary effusion lymphoma and some forms of Castleman's disease. KSHV is a rhadinovirus, and like other rhadinoviruses, it has an extensive array of regulatory genes obtained from the host cell genome. These pirated KSHV proteins include homologues to cellular CD21, three different β–chemokines, IL–6, BCL–2, several different interferon regulatory factor homologues, Fas–ligand ICE inhibitory protein (FLIP), cyclin D and a G–protein–coupled receptor, as well as DNA synthetic enzymes including thymidylate synthase, dihydrofolate reductase, DNA polymerase, thymidine kinase and ribonucleotide reductases. Despite marked differences between KSHV and Epstein–Barr virus, both viruses target many of the same cellular pathways, but use different strategies to achieve the same effects. KSHV proteins have been identified which inhibit cell–cycle regulation checkpoints, apoptosis control mechanisms and the immune response regulatory machinery. Inhibition of these cellular regulatory networks appears to be a defensive means of allowing the virus to escape from innate antiviral immune responses. However, due to the overlapping nature of innate immune and tumour–suppressor pathways, inhibition of these regulatory networks can lead to unregulated cell proliferation and may contribute to virus–induced tumorigenesis.

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