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Dose-dependent cell cycle arrest and apoptosis in HER2 breast cancer cells by177Lu-CHX-A“-DTPA-Trastuzumab


1 Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
2 Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Radiopharmaceuticals Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Mumbai, Maharashtra, India

Correspondence Address:
Mythili Kameswaran,
Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Trombay, Mumbai - 400 085, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_20_19

Background: Trastuzumab is a Food and Drug Administration-approved humanized monoclonal antibody which targets the extracellular domain of human epidermal growth factor receptor 2 (HER2) receptor overexpressed on HER2-positive breast cancer cells. The combination of Lutetium-177 (177 Lu) (t½= 6.7 days, Eβmax497 keV (78.6%) and trastuzumab makes it a suitable targeting agent for radioimmunotherapy. In preclinical and clinical studies,177 Lu-Trastuzumab has proven to be effective for the treatment of HER2-positive malignancies such as breast and ovarian cancer. Objectives: In this study, we report the mechanism of action of177 Lu-CHX-A“-diethylenetriaminepentaacetic acid (DTPA)-trastuzumab at the cellular and molecular level by performing various in vitro assays in HER2-positive MDA-MB-453 breast cancer cells. Materials and Methods: Trastuzumab was conjugated to the bifunctional chelating agent (BFCA) para-isothiocyanatobenzyl-DTPA and radiolabeled with177 Lu. In vitro cell binding studies were carried out in MDA-MB-453 cells to confirm the specificity of the complex toward the receptor. Cellular toxicity, cell cycle, and cell death analysis were also performed for exploring the potential of the radioimmunoconjugate at cellular and molecular level. Results: In vitro cell binding studies showed a maximum binding of 10.7 ± 0.1% which reduced to 2.9 ± 0.1% on coincubation with unlabeled antibody. Our study revealed that the cellular toxicity was dose dependent, and mode of cell death was predominantly by apoptosis. The radioimmunoconjugate retarded the cell in the S phase of cell cycle with two-fold increase in G2/M arrest which justifies the enhanced apoptosis at higher doses. Conclusions: The study revealed that the formulation can execute a dose-dependent cellular toxicity through induction of apoptosis.


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