Abstract
Ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (γ‐H2AX) is a reliable and sensitive technique to monitor external beam IR-induced DSBs in peripheral blood lymphocytes (PBL). Here, we investigated whether γ-H2AX could be used as an in vivo marker to assess normal tissue toxicity after extended internal irradiation with 177Lu-DOTA-octreotate peptide receptor radionuclide therapy (LuTate PRRT) of neuroendocrine tumors. Methods: We analyzed the kinetics of γ-H2AX foci in PBL of 11 patients undergoing PRRT. The number of γ-H2AX foci was determined before and up to 72h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow and tumor and with subsequent PBL reduction. Results: Decrease in 177Lu activity in blood with time followed a bi-exponential kinetic pattern, with approximately 90% of circulating activity in blood cleared within 2h. Absorbed dose to blood but not to spleen or bone marrow, correlated with the administered 177Lu activity. PRRT increased γ-H2AX foci in lymphocytes in all patients, relative to pre-therapy values. The response varied significantly between patients, but the average number of foci indicated a general trend towards increase at 0.5-4h with subsequent decrease by 24-72h post-treatment. The peak foci number correlated with the absorbed dose to tumor and bone marrow and the extent of PBL reduction. Conclusion: γ-H2AX can be exploited in the LuTate PRRT as a biomarker of PBL cytotoxicity. Long-term follow-up studies investigating whether elevated residual γ-H2AX values are associated with acute myelotoxicity and secondary blood malignancy may be worthwhile.
- Neuroendocrine
- Radiobiology/Dosimetry
- Radionuclide Therapy
- γ-H2AX
- 177Lu-octreotate
- DNA damage
- PRRT
- normal tissue toxicity
- Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.