Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors

Abstract

We investigated the possibility of using a pharmacologic agent to modulate viral gene expression in order to target radiotherapy to tumor tissue. In a murine xenograft model, we had previously shown targeting of [125I]2'-fluoro-2'-deoxy-beta-D-5-iodouracilarabinofuranoside ([125I]FIAU) to tumors engineered to express the Epstein-Barr virus (EBV)-thymidine kinase (TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [131I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK, as well as with naturally-infected EBV tumor cell lines. Burkitt's lymphoma and gastric carcinoma required activation of viral gene expression by pretreatment with bortezomib. Marked changes in tumor growth could also be achieved in naturally-infected Kaposi's sarcoma herpesvirus (KSHV) tumors following bortezomib activation. Bortezomib-induced enzyme-targeted radiation (BETR) therapy illustrates the possibility of pharmacologically modulating tumor gene expression to effect targeted radiotherapy.

High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

“…Evaluation of additional cytotoxic approaches specifically targeting cells expressing KSHV lytic genes appears warranted in KSHV-MCD. 51 As our understanding of this rare disease continues to improve, durable remissions for the majority of HIV-infected patients with KSHV-MCD obtained through the use of targeted therapy appear to be an attainable goal.…”

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

“…Bortezomib was reported to induce EBV lytic cycle in EBV-positive Burkitt lymphoma and gastric carcinoma cells (25). Induction of EBV lytic cycle by bortezomib could activate the radioisotope [ 125 I]2 0 -fluoro-2 0 -deoxy-b-D-5-iodouracil-arabinofuranoside to selectively suppress the growth of Burkitt lymphoma xenografts in severe combined immunodeficient (SCID) mice (25). Our laboratory has previously shown that SAHA could significantly induce viral lytic cycle in EBV-positive gastric carcinoma and NPC cells and mediates enhanced apoptosis (11,12).…”

Lymphoepithelioma-like gastric carcinoma located in the lesser curvature of the gastric body: A case report and review of the literature

“…Therapeutic approaches require further research on virus-host interactions in EBV-associated neoplasms (16). Since viral replication is inhibited by promoter methylation in EBV DNA, demethylating agents, such as 5-azacytidine, may induce lytic infection by EBV, leading to lysis of infected cells (17).…”