Analysis of 177Lu-DOTA-Octreotate Therapy-Induced DNA Damage in Peripheral Blood Lymphocytes of Patients with Neuroendocrine Tumors

Ionizing radiation induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability, and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (gamma-H2A) is a reliable and sensitive technique to monitor external-beam ionizing radiation induced DSBs in peripheral blood lymphocytes (PBLs). Here, we investigated whether gamma-H2AX could be used as an in vivo marker to assess normal-tissue toxicity after extended internal irradiation with Lu-177-DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. Methods: We analyzed the kinetics of gamma-H2AX foci in PBLs of 11 patients undergoing PRRT. The number of gamma-H2AX foci was determined before and up to 72 h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow, and tumor and with subsequent PBL reduction. Results: The decrease in Lu-177 activity in blood with time followed a biexponential kinetic pattern, with approximately 90% of circulating activity in blood cleared within 2 h. Absorbed dose to blood, but not to spleen or bone marrow, correlated with the administered Lu-177 activity. PRRT increased gamma-H2AX foci in lymphocytes in all patients, relative to pretherapy values. The response varied significantly between patients, but the average number of foci indicated a general trend toward an increase at 0.5-4 h with a subsequent decrease by 24-72 h after treatment. The peak number of foci correlated with the absorbed dose to tumor and bone marrow and the extent of PBL reduction. Conclusion: gamma-H24X can be exploited in the LuTate PRRT as a biomarker of PBL cytotoxicity. Long-term follow-up studies investigating whether elevated residual gamma-H2AX values are associated with acute myelotoxicity and secondary blood malignancy may be worthwhile.