Radioimmunotherapy with α-Particle–Emitting 213Bi-C-Functionalized <i>trans</i>-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy

Kelly, Marcus P.; Lee, Fook-Thean; Tahtis, Kiki; Smyth, Fiona E; Brechbiel, Martin W.; Scott, Andrew M.

doi:10.1158/1078-0432.ccr-07-1071

Cited by 34 publications

(19 citation statements)

References 34 publications

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“…Various studies also reported that high LET α-particle immunoconjugates induced apoptosis, and that the mode of cell death triggered by α-particle emitters seemed to be dependent on the type of cells irradiated (42–46). …”

Section: Discussionmentioning

confidence: 98%

212Pb-Radioimmunotherapy Induces G2 Cell-Cycle Arrest and Delays DNA Damage Repair in Tumor Xenografts in a Model for Disseminated Intraperitoneal Disease

Yong

Milenic

Baidoo

et al. 2012

Molecular Cancer Therapeutics

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In pre-clinical studies, targeted radioimmunotherapy using 212Pb-TCMC-trastuzumab as an in vivo generator of the high energy α-particle emitting radionuclide 212Bi is proving an efficacious modality for the treatment of disseminated peritoneal cancers. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T i.p. xenografts were treated with 212Pb-TCMC-trastuzumab and compared to the non-specific control 212Pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. 212Pb-TCMC-trastuzumab treatment induced significantly more apoptosis and DNA double stranded breaks (DSBs) at 24 h. Rad51 protein expression was down-regulated, indicating delayed DNA double strand damage repair compared to 212Pb-TCMC-HuIgG, the non-specific control. 212Pb-TCMC-trastuzumab treatment also caused G2/M arrest, depression of the S phase fraction and depressed DNA synthesis that persisted beyond 120 h. In contrast, the effects produced by 212Pb-TCMC-HuIgG appeared to rebound by 120 h. In addition, 212Pb-TCMC-trastuzumab treatment delayed open chromatin structure and expression of p21 until 72 h, suggesting a correlation between induction of p21 protein and modification in chromatin structure of p21 in response to 212Pb-TCMC-trastuzumab treatment. Taken together, increased DNA DSBs, impaired DNA damage repair, persistent G2/M arrest, and chromatin remodeling were associated with 212Pb-TCMC-trastuzumab treatment and may explain its increased cell killing efficacy in the LS-174T i.p. xenograft model for disseminated intraperitoneal disease.

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Section: Discussionmentioning

confidence: 98%

212Pb-Radioimmunotherapy Induces G2 Cell-Cycle Arrest and Delays DNA Damage Repair in Tumor Xenografts in a Model for Disseminated Intraperitoneal Disease

Yong

Milenic

Baidoo

et al. 2012

Molecular Cancer Therapeutics

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“…In another study, γ-H2AX levels increased in cultured tumour cells confirming the genotoxic effect of radioimmunotherapy with alpha-particle emitting 213 Bi. The anti-tumour efficacy of this therapy was confirmed in a mouse model [95]. However, in a real clinical situation, during radionuclide therapy, directly targeted tumours are often not accessible; rather, normal tissue response to a circulating radionuclide (direct or bystander) can be monitored.…”

Section: Monitoring Effects Of Radionuclide Therapymentioning

confidence: 99%

Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research

et al. 2012

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Formation of γ-H2AX in response to DNA double stranded breaks (DSBs) provides the basis for a sensitive assay of DNA damage in human biopsies. The review focuses on the application of γ-H2AX-based methods to translational studies to monitor the clinical response to DNA targeted therapies such as some forms of chemotherapy, external beam radiotherapy, radionuclide therapy or combinations thereof. The escalating attention on radiation biodosimetry has also highlighted the potential of the assay including renewed efforts to assess the radiosensitivity of prospective radiotherapy patients. Finally the γ-H2AX response has been suggested as a basis for an in vivo imaging modality.

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“…Several clinical trials have focused on or included subjects with PC (7–16). Importantly, unlike some other solid tumors, a well-established, specific cell-surface antigen has been identified: prostate-specific membrane antigen (PSMA) (17–19).…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Recovery and Subsequent Chemotherapy Following Radiolabeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Men with Metastatic Castration-Resistant Prostate Cancer

et al. 2013

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Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin’s lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing 177Lu- or 90Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT.

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Radioimmunotherapy with α-Particle–Emitting 213Bi-C-Functionalized trans-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy

Cited by 34 publications

References 34 publications

212Pb-Radioimmunotherapy Induces G2 Cell-Cycle Arrest and Delays DNA Damage Repair in Tumor Xenografts in a Model for Disseminated Intraperitoneal Disease

212Pb-Radioimmunotherapy Induces G2 Cell-Cycle Arrest and Delays DNA Damage Repair in Tumor Xenografts in a Model for Disseminated Intraperitoneal Disease

Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research

Bone Marrow Recovery and Subsequent Chemotherapy Following Radiolabeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Men with Metastatic Castration-Resistant Prostate Cancer

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