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Cancer Chemother Pharmacol. 2017 Sep;80(3):517-526. doi: 10.1007/s00280-017-3377-7. Epub 2017 Jul 13.

Doxycycline and its quaternary ammonium derivative for adjuvant therapies of chondrosarcoma.

Author information

1
Centre Jean Perrin, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, 63000, Clermont-Ferrand, France.
2
Centre Jean Perrin, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, 63000, Clermont-Ferrand, France. magali.vivier@uca.fr.
3
Département d'anatomo-pathologie, Centre Jean Perrin, 63000, Clermont-Ferrand, France.
4
IRM 3T-Recherche-CHU Gabriel Montpied, 63000, Clermont-Ferrand, France.
5
CNRS, UMR 6023, LMGE, 63177, Aubière, France.
6
Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses primitives, UMR S957 INSERM, Nantes Atlantique Universités, 44000, Nantes, France.

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.

KEYWORDS:

Adjuvant therapy; Chondrosarcoma; Doxycycline; MMP inhibitors; Quaternary ammonium function

PMID:
28707014
DOI:
10.1007/s00280-017-3377-7
[Indexed for MEDLINE]

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