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13.07.2017 | Original Article

Doxycycline and its quaternary ammonium derivative for adjuvant therapies of chondrosarcoma

verfasst von: Imen Miladi, Magali Vivier, Marie-Mélanie Dauplat, Morgane Chatard, Sophie Besse, Aurélien Vidal, Karine Chassain, Betty Jean, Christiane Forestier, Jean-Michel Chezal, Francoise Rédini, Francoise Degoul, Elisabeth Miot-Noirault

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2017

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Abstract

Purpose

This study was conducted during the development of innovative treatment targeting the microenvironment of chondrosarcoma. In this context, MMP inhibitors were conjugated with a quaternary ammonium (QA) function as a targeting ligand to proteoglycans of chondrosarcoma extracellular matrix. Here we report the proof of concept of this strategy applied to the MMP13 inhibitor, doxycycline (Dox).

Methods

A quaternary ammonium derivative of the MMP13 inhibitor doxycycline (QA-Dox) was synthesized, and its anticancer activity was evaluated in the Swarm rat chondrosarcoma (SRC) model compared with the parent drug doxycycline, in vitro and in vivo. In vivo, dox and QA-Dox efficiency was assessed at equimolar doses according to a q4dx4 schedule by monitoring tumour volume by MRI and PG-targeted scintigraphy. Molecular mechanism (MMP13 expression, proteoglycan level) and histology studies were performed on tumours.

Results

The link of QA targeting function to Dox maintained the MMP13 inhibitory activity in vitro. Interestingly, the bacteriostatic activity was lost. SRC cells incubated with both drugs were blocked in S and G2 M phases. Tumour growth inhibition (confirmed by histology) was observed for both Dox and QA-Dox. Undesirable blood effects (leukocyte decrease) were reduced when Dox was targeted to tumour tissue using the QA function.

Conclusions

In the SRC model, the MMP13 inhibitor Dox and its QA derivative are promising as adjuvant therapies for chondrosarcoma management.

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Titel: Doxycycline and its quaternary ammonium derivative for adjuvant therapies of chondrosarcoma
verfasst von: Imen Miladi
Magali Vivier
Marie-Mélanie Dauplat
Morgane Chatard
Sophie Besse
Aurélien Vidal
Karine Chassain
Betty Jean
Christiane Forestier
Jean-Michel Chezal
Francoise Rédini
Francoise Degoul
Elisabeth Miot-Noirault
Publikationsdatum: 13.07.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2017
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3377-7

Springer Medizin

Doxycycline and its quaternary ammonium derivative for adjuvant therapies of chondrosarcoma