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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 to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [125I]2′-fluoro-2′-deoxy-β-D-5-iodouracil-arabinofuranoside ([125I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-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. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.

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Figure 1: [125I]FIAU tissue distribution in a mouse xenograft model.
Figure 2: Tumor growth curves in xenografts engineered to express EBV-TK or control tumors.
Figure 3: Tumor growth curves in mouse xenografts.
Figure 4: [125I]FIAU SPECT imaging of tumors after bortezomib treatment.

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Acknowledgements

We thank S.D. Hayward (Johns Hopkins School of Medicine) for Burkitt's lymphoma cell lines and G. Hayward (Johns Hopkins School of Medicine) for primary effusion lymphoma cell lines. We thank R. Wahl, S.D. Hayward, W.-S. Hsieh and M. Shamay for suggestions; S. Bonekamp, K.F. Kwok and J. Yu for reconstruction of imaging data; S. Wang for assistance in the syntheses of [125I]FIAU and [131I]FIAU; G. Green for assistance with mouse imaging and therapy; and S. Nimmagadda for assistance with mouse experiments. This work was supported by grants from the US National Institutes of Health (NIH/NCI P50 CA96888, P01 CA113239 and U24 CA92871).

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Authors

Contributions

D.-X.F. designed and performed mouse imaging and therapy experiments, Y.T. designed and performed mouse imaging experiments, J.C. assisted with the design and interpretation of mouse experiments, J.J.F. synthesized radiotracers and carried out imaging and image analysis, C.A.F. synthesized radiotracers and assisted with imaging and image analysis, J.-M.C. designed and performed mouse experiments involving gastric carcinoma xenografts, R.F.H. carried out dosimetry analysis, M.F. made the transplantable gastric carcinoma xenografts available and assisted in the design of experiments, G.S. assisted in the design and interpretation of experiments and in the writing of the manuscript, J.K. provided statistical guidance, M.G.P. assisted in the design and interpretation of experiments and editing of the manuscript and R.F.A. designed and conceptualized the approach, analyzed and interpreted data and wrote the manuscript. The final version of the manuscript was seen and approved by all authors.

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Correspondence to Richard F Ambinder.

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Fu, DX., Tanhehco, Y., Chen, J. et al. Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors. Nat Med 14, 1118–1122 (2008). https://doi.org/10.1038/nm.1864

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