212Pb-radioimmunotherapy potentiates paclitaxel-induced cell killing efficacy by perturbing the mitotic spindle checkpoint

Yong, Kwon Joong; Milenic, Diane E.; Baidoo, K E; Brechbiel, Martin W.

doi:10.1038/bjc.2013.189

Cited by 23 publications

(28 citation statements)

References 37 publications

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“…Upon incubation with paclitaxel alone, BUBR1 expression was found to be elevated. The increase in expression of BUBR1 was reversed at the transcription level upon subsequent treatment with 212 Pb-trastuzumab consistent with an earlier study from this laboratory [15] . Topoisomerase II helps to bring about a high order of compaction of chromatin to form condensed mitotic chromosomes [28] .…”

Section: Resultssupporting

confidence: 90%

“…Addition of paclitaxel to the treatment protocol resulted in greater therapeutic efficacy in the LS-174T i.p. tumor xenograft model [15] . The inclusion of paclitaxel in the regimen was found to increase mitotic catastrophe and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, gene modulations associated with the cytocidal response have not been clearly defined following exposure of cells to α-particle RIT combined with paclitaxel [13] , [14] . A recent report from this laboratory showed that paclitaxel potentiates 212 Pb-trastuzumab cytotoxicity, in part, by perturbing the mitotic spindle checkpoint [15] . Gene expression profiling provides a potentially powerful approach towards understanding the molecular basis of the cellular response to therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

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Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel

et al. 2014

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To better understand the molecular basis of the enhanced cell killing effected by the combined modality of paclitaxel and 212Pb-trastuzumab (Pac/212Pb-trastuzumab), gene expression in LS-174T i.p. xenografts was investigated 24 h after treatment. Employing a real time quantitative PCR array (qRT-PCR array), 84 DNA damage response genes were quantified. Differentially expressed genes following therapy with Pac/212Pb-trastuzumab included those involved in apoptosis (BRCA1, CIDEA, GADD45α, GADD45γ, GML, IP6K3, PCBP4, PPP1R15A, RAD21, and p73), cell cycle (BRCA1, CHK1, CHK2, GADD45α, GML, GTSE1, NBN, PCBP4, PPP1R15A, RAD9A, and SESN1), and damaged DNA repair (ATRX, BTG2, EXO1, FEN1, IGHMBP2, OGG1, MSH2, MUTYH, NBN, PRKDC, RAD21, and p73). This report demonstrates that the increased stressful growth arrest conditions induced by the Pac/212Pb-trastuzumab treatment suppresses cell proliferation through the regulation of genes which are involved in apoptosis and damaged DNA repair including single and double strand DNA breaks. Furthermore, the study demonstrates that 212Pb-trastuzumab potentiation of cell killing efficacy results from the perturbation of genes related to the mitotic spindle checkpoint and BASC (BRCA1-associated genome surveillance complex), suggesting cross-talk between DNA damage repair and the spindle damage response.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel

et al. 2014

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“…Ideally this approach delays the delivery of the radioactivity until the ratio of tumor-bound to nontumor-bound targeting agent has reached its maximum. [726][727][728][729][730][731] Polyethylene glycol (PEG) modification of targeting agents is an example of an optimization strategy under study that provides multiple carrying sites for molecules such as radiosensitizers. Thus, the pretargeting approach has the potential to improve tumor-to-normal tissue ratios several fold over that achieved with directly labeled antibodies by minimizing circulation time of unbound radionuclide.…”

Section: Critical Referencesmentioning

confidence: 99%

Targeted Radionuclide Therapy

Jurcic¹,

Wong²,

Knox³

et al. 2016

Clinical Radiation Oncology

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“…Consistent with this observation, interference with a functional Aurora B, which reduces the affinity of BubR1 for kinetochores, was observed in response to this treatment regimen. Therefore, the impairment of the mitotic spindle checkpoint may lead to death of tumor cells [66]. …”

Section: Mechanistic Studies Of Targeted 212pbmentioning

confidence: 99%

Application of <sup>212</sup>Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

Yong¹,

Brechbiel

2015

medicalScience

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Targeted α-particle therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. 212Pb is the longer-lived parent radionuclide of 212Bi and serves as an in vivo generator of 212Bi. 212Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of 212Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of 212Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of 212Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.

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212Pb-radioimmunotherapy potentiates paclitaxel-induced cell killing efficacy by perturbing the mitotic spindle checkpoint

Cited by 23 publications

References 37 publications

Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel

Impact of α-Targeted Radiation Therapy on Gene Expression in a Pre-Clinical Model for Disseminated Peritoneal Disease when Combined with Paclitaxel

Targeted Radionuclide Therapy

Application of <sup>212</sup>Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

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