Analysis of <sup>177</sup>Lu-DOTA-Octreotate Therapy–Induced DNA Damage in Peripheral Blood Lymphocytes of Patients with Neuroendocrine Tumors

Denoyer, Delphine; Lobachevsky, Pavel; Jackson, Price; Thompson, Margaret A.; Martin, Olga A.; Hicks, Rodney J.

doi:10.2967/jnumed.114.145581

Cited by 51 publications

(48 citation statements)

References 27 publications

(42 reference statements)

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“…There still is a limited number of publications investigating the effect of DSB induction after radionuclide therapy or diagnostics (16,(18)(19)(20)22). However, nuclear medicine treatments involve systemic internal irradiation as compared with external irradiation (e.g., in radiotherapy).…”

Section: Discussionmentioning

confidence: 99%

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DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy

et al. 2015

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The aim of the study was to investigate DNA double-strand break (DSB) formation and its correlation to the absorbed dose to the blood in patients with surgically treated differentiated thyroid cancer undergoing their first radioiodine therapy for remnant ablation. Methods: Twenty patients were included in this study. At least 7 peripheral blood samples were obtained before and between 0.5 and 120 h after administration of radioiodine. From the timeactivity curves of the blood and the whole body, residence times for the blood self-irradiation and the irradiation from the whole body were determined. Peripheral blood lymphocytes were isolated, ethanol-fixed, and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was analyzed as a function of the absorbed dose to the blood and compared with an in vitro calibration curve for 131 I and 177 Lu established previously in our institution. Results: The average number of radiation-induced foci (RIF) per cell increased over the first 3 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 2 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time points, RIF numbers diminished, along with dropping dose rates, indicating progression of DNA repair. Individual patient data were characterized by a linear dosedependent increase and a biexponential response function describing a fast and a slow repair component. Conclusion: With the experimental results and model calculations presented in this work, a dose-response relationship is demonstrated, and an analytic function describing the time course of the in vivo damage response after internal irradiation of patients with 131 I is established.Key Words: γ-H2AX; 53BP1; biological dosimetry; radioiodine therapy; DTC; absorbed dose to blood; dose response; DSB focus assay; DNA damage; 131 I; differentiated thyroid cancer Nucl Med 2016; 57:173-179 DOI: 10.2967/jnumed.115.164814 Af ter total thyroidectomy for differentiated thyroid cancer (DTC), patients generally receive one or more treatments with high activities of 131 I. The purpose of the initial radioiodine therapy after surgery is to ablate remnant thyroid tissue and to effectively treat any iodine-avid metastases (1,2). Because patients with DTC generally do not undergo chemotherapy or other radiotherapy before radioiodine therapy, this patient group is ideally suited for the investigation of the DNA damage in blood lymphocytes induced by protracted, nearly homogeneous whole-body irradiation. In this setting, all organs, including the blood, are irradiated by b-particles emitted from circulating 131 I and from penetrating g-radiation originating from activity dispersed throughout the body. The absorbed dose and dose rate to the blood is assessed by defining the timeactivity curves in the blood and the whole body, integrating the corresponding time-activity curves and calculating the absorbed dose acco...

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Section: Discussionmentioning

confidence: 99%

“…More recent studies addressed g-H2AX foci formation after 177 Lu therapy of neuroendocrine tumors (16,20). In these studies the authors observed elevated levels of radiation-induced DNA damage foci after treatment, but a clear dose-response relationship could only be established in one study (16).…”

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DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy

et al. 2015

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“…A recent paper described the use of a g-H2AX-foci assay as a predictor of normal-tissue toxicity after PRRT (24). Genetic components can also predict disease stage and response to therapy (25).…”

Section: Innovative Methods As Predictors Of Therapeutic Responsementioning

confidence: 99%

Radiopeptides for Imaging and Therapy: A Radiant Future

2015

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“…To move toward a more modern and personalized assessment of risk, in future evaluation of therapy, individual radiosensitivity will need to be assessed by specific biomarkers, such as chromosomal screening of bone marrow of patients potentially at risk, γ-H2AX assays (Denoyer et al 2015), and genetic testing. An unmet need is the availability of pre-or intratherapeutic assessment of circulating transcriptional markers to predetermine or delineate impending neoplastic marrow events.…”

Section: :8mentioning

confidence: 99%

Myeloid neoplasms after chemotherapy and PRRT: myth and reality

Bodei

Modlin

Luster

et al. 2016

Endocrine-Related Cancer

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Peptide receptor radionuclide therapy (PRRT) with 90 Y-octreotide or 177 Lu-octreotate is an effective treatment for inoperable or metastatic neuroendocrine tumors (NETs), particularly well-differentiated gastroenteropancreatic or bronchopulmonary NETs. PRRT is generally extremely well tolerated, with modest toxicity to target organs, kidney and bone marrow. Nevertheless, a priori concerns regarding long-term effects lead clinicians such as Brieau and coworkers, in this ERC issue, to ascribe to the combination of alkylating agents and PRRT the apparently high occurrence (n = 4) of myeloproliferative events (therapy-related myeloid neoplasms (t-MNs)) in a small cohort of 20 progressive, advanced digestive NETs treated with PRRT after chemotherapy. Anecdotal reports of myelotoxic events should be placed in the correct perspective of larger series, where the reported incidence of these events is ~2%, with the aim of promoting a balanced awareness of the issue and unbiased and reasonable overall conclusions. For a comprehensive definition of the issue, we provide an evaluation of the occurrence of t-MN in patients treated with various myelotoxic treatments. L Bodei et al. t-MN: myth and reality 23:8 Commentary

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

Cited by 51 publications

References 27 publications

DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy

DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy

Radiopeptides for Imaging and Therapy: A Radiant Future

Myeloid neoplasms after chemotherapy and PRRT: myth and reality

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

Cited by 51 publications

References 27 publications

DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy

DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy

Radiopeptides for Imaging and Therapy: A Radiant Future

Myeloid neoplasms after chemotherapy and PRRT: myth and reality

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Product

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