Unveiling the intra-tumor fate of trastuzumab deruxtecan in a xenograft model to support its mechanism of action.
Drug Metab Pharmacokinet
; 56: 101001, 2024 Jun.
Article
en En
| MEDLINE
| ID: mdl-38643548
ABSTRACT
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate used for cancer treatment comprising an anti-human epidermal growth factor receptor type 2 (HER2) antibody and the topoisomerase I inhibitor DXd. The present study investigated the intratumor fate of T-DXd. Fluorescence-labeled T-DXd was found to accumulate in tumors of HER2-positive tumor xenograft mice and was observed to be distributed within lysosomes of in vitro tumor cells in accordance with their HER2 expression. DXd was released by cysteine proteases, including cathepsins, in lysosomal fractions in vitro in response to the pH. Tumor slices obtained from HER2-positive tumor xenograft mice treated with T-DXd were examined by semi-quantitative and three-dimensional immunohistochemical assays using phosphor-integrated dots, which visualized DXd-related signals in the nucleus, the site of topoisomerase I inhibition. In addition, based on the data showing the antibody component of T-DXd barely distributed in the nucleus, it was suggested that the DXd-related signals detected in the nucleus were predominantly derived from free DXd. These observations help support the mode of action of T-DXd from the perspective of drug disposition.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Camptotecina
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Inmunoconjugados
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Ensayos Antitumor por Modelo de Xenoinjerto
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Trastuzumab
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Drug Metab Pharmacokinet
Asunto de la revista:
FARMACOLOGIA
/
METABOLISMO
Año:
2024
Tipo del documento:
Article