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Int. J. Mol. Sci. 2016, 17(5), 736; doi:10.3390/ijms17050736

Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive MSC-1002, Bethesda, MD 20892, USA
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Academic Editor: Guillermo T. Sáez
Received: 25 March 2016 / Revised: 28 April 2016 / Accepted: 7 May 2016 / Published: 16 May 2016
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)
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Abstract

Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β-particle RIT for the management of intraperitoneal disease. View Full-Text
Keywords: 177Lu-Radioimmunotherapy (RIT); DNA double strand breaks; DNA repair; apoptosis; micrometastatic disease 177Lu-Radioimmunotherapy (RIT); DNA double strand breaks; DNA repair; apoptosis; micrometastatic disease
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Yong, K.J.; Milenic, D.E.; Baidoo, K.E.; Brechbiel, M.W. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts. Int. J. Mol. Sci. 2016, 17, 736.

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