<sup>213</sup>Bi-Labeled Prostate-Specific Membrane Antigen-Targeting Agents Induce DNA Double-Strand Breaks in Prostate Cancer Xenografts

Nonnekens, Julie; Chatalic, Kristell L.S.; Molkenboer-Kuenen, Janneke D.M.; Beerens, Cecile; Bruchertseifer, Frank; Morgenstern, Alfred; Veldhoven-Zweistra, Joke; Schottelius, Margret; Wester, Hans‐Jürgen; Gent, Dik C. van; Weerden, Wytske M. van; Boerman, Otto C.; Jong, Marion de; Heskamp, Sandra

doi:10.1089/cbr.2016.2155

Cited by 51 publications

(50 citation statements)

References 30 publications

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“…We noted that the frequency of α-tracks represents a suitable parameter for biological dose estimation, which is in accordance with recent γ-H2AX studies on DNA damage after internal or external irradiation with α-particles using the γ-H2AX assay 24 , 33 , 34 , 42 . We observed that γ-H2AX was a more robust marker for α-tracks than 53BP1, in agreement with previous observations that γ-H2AX is an indirect DSB marker in the chromatin surrounding DSBs in high LET particle tracks 38 , 43 , 44 .…”

Section: Discussionsupporting

confidence: 90%

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

Schumann

Eberlein

Muhtadi

et al. 2018

Sci Rep

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Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.

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Section: Discussionsupporting

confidence: 90%

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

Schumann

Eberlein

Muhtadi

et al. 2018

Sci Rep

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“…Chatalic et al [100] reported the 111 In-DTPA-labeled engineered expression-modified nanobody JVZ-007, with a myc-tag and cys tag ( 111 In-JVZ007-c-myc-his and 111 InJVZ007-cys), which displayed good PSMA-positive tumor-targeting capability with rapid blood clearance in vivo. The therapeutic usefulness of the PSMA nanobody was evaluated for the first time in 2017 [101]. This study revealed an efficient and rapid prostate tumor-targeting by the JVZ-008 nanobody labeled with 213 Bi ( 213 Bi-JVZ-008) in mice bearing PSMA-positive LNCaP xenograft.…”

Section: Minibodies Diabodies Single-chain Variable Region Fragmentmentioning

confidence: 99%

Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives

et al. 2020

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Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. Due to the significant mortality and morbidity rate associated with the progression of this disease, there is an urgent need for new and targeted treatments. In this review, we summarize the recent advances in research on identification of prostate tissue-specific antigens for targeted therapy, generation of highly specific and selective molecules targeting these antigens, availability of therapeutic radionuclides for widespread medical applications, and recent achievements in the development of new-generation small-molecule inhibitors and antibody-based strategies for targeted prostate cancer therapy with alpha-, beta-, and Auger electron-emitting radionuclides.

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“…To our knowledge, few accounts of preclinical therapy studies of PSMA-targeting a-radioligand therapeutics have been reported, and none have shown such a profound antitumor effect. 213 Bi-PSMA-I&T was shown to induce double-strand breaks in LNCaP xenograft tumor cells, but tumor uptake was low (5.75 6 2.70 %ID/g at 1 h after injection), tumor-to-kidney ratio poor (0.19 6 0.10), and relatively few a-tracks and double-strand breaks were evident in the tumor 24 h after injection (34). An investigation of 211 At-6 was conducted in mice bearing subcutaneous PC3-PIP tumors with a maximum initial volume of 200 mm 3 (31).…”

Section: Discussionmentioning

confidence: 99%

A Single Dose of ²²⁵Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model

et al. 2018

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Promising biochemical responses to 225 Ac-prostate-specific membrane antigen (PSMA) 617, even in patients who are refractory to βparticle radiation, illustrate the potential of targeted α-therapy for the treatment of metastatic castration-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. To fully harness the potential of targeted α-therapy, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Methods: 225 Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37, 74, and 148 kBq of 225 Ac-RPS-074 and compared with positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1,500 mm 3 . Results: 225 Ac-RPS-074 was labeled in greater than 98% radiochemical yield and showed high (.10% injected dose/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h after injection and cleared by 7 d. The tumor-tokidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6 of 7 tumors, with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7 of 7 tumors, but from 42 d, 6 of 7 experienced significant regrowth. The 37-kBq group experienced a survival benefit relative to the negative control but not compared with the positive control group. Conclusion: A single dose of 148 kBq of 225 Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal-tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted α-therapeutic. Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP 225 A Single Dose of http://jnm.snmjournals.org/content/60/5/649 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

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²¹³Bi-Labeled Prostate-Specific Membrane Antigen-Targeting Agents Induce DNA Double-Strand Breaks in Prostate Cancer Xenografts

Abstract: Bi-PSMA I&T and Bi-JVZ-008 showed efficient and rapid tumor targeting and produced DSBs in PSMA-expressing LNCaP cells and xenografts. These promising results require further evaluation ofBi-labeled agents with regard to their therapeutic efficacy and toxicity for PCa therapy.

Cited by 51 publications

References 30 publications

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives

A Single Dose of ²²⁵Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model

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213Bi-Labeled Prostate-Specific Membrane Antigen-Targeting Agents Induce DNA Double-Strand Breaks in Prostate Cancer Xenografts

Abstract: Bi-PSMA I&T and Bi-JVZ-008 showed efficient and rapid tumor targeting and produced DSBs in PSMA-expressing LNCaP cells and xenografts. These promising results require further evaluation ofBi-labeled agents with regard to their therapeutic efficacy and toxicity for PCa therapy.

Cited by 51 publications

References 30 publications

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives

A Single Dose of 225Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model

Contact Info

Product

Resources

About

²¹³Bi-Labeled Prostate-Specific Membrane Antigen-Targeting Agents Induce DNA Double-Strand Breaks in Prostate Cancer Xenografts

A Single Dose of ²²⁵Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model