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Quaternary ammonium-melphalan conjugate for anticancer therapy of chondrosarcoma: in vitro and in vivo preclinical studies

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Summary

Cartilage tumours present ongoing therapeutic challenges due to their chondrogenic extracellular matrix that potentially hampers drug delivery, their low percentage of dividing cells, and their poor vascularity. In this context, and based on the affinity of the quaternary ammonium moiety for proteoglycans (PG), we developed a strategy that uses the quaternary ammonium function to selectively deliver DNA alkylating agents to the cartilage tumour tissue. We engineered the quaternary ammonium derivative of melphalan (Mel-AQ) and assessed its antitumoural activity in vitro and in vivo. In vitro, micromolar concentrations of Mel-AQ inhibited the proliferation of human HEMC-SS chondrosarcoma and Saos-2 osteosarcoma cell lines. Moreover, 24-h incubation with 20 μM Mel-AQ induced a 2.5-fold increase in S population and a 1.5-fold increase in subG0G1 population compared to controls. In vivo, Mel-AQ demonstrated antitumour activity in the orthotopic model of primary Swarm rat chondrosarcoma. When given to chondrosarcoma-bearing rats (three doses of 16 μmol/kg at days 8, 12 and 16 post-implant), Mel-AQ demonstrated an optimal antitumour effect at day 43, when tumour cell growth inhibition peaked at 69%. Interestingly, the treatment protocol was proved well tolerated, since the animals showed no weight loss over the course of the study. This antitumoural effect was assessed in vivo by scintigraphic imaging using 99mTc-NTP 15–5 developed in our lab as a PG-targeting radiotracer, and tumour tissue was analyzed at study-end by biochemical PG assay with Alcian blue staining. Mel-AQ treatment led to a significant decrease in the PG content of tumoural tissue. These experimental results highlighted the promising antitumour potential of Mel-AQ as a PG-targeting strategy for therapeutic management of chondrosarcoma.

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Financial support

Institut National du Cancer (NoRO7022NN), Ligue Contre le Cancer Auvergne Région, Innovation Regional Fund (FRI2, OSEO), State-Region Planning Contract (CPER)

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Authors and Affiliations

  1. UMR 990 INSERM/ UdA, Université d’Auvergne, Rue Montalembert, BP184, 63005, Clermont Ferrand Cedex, France

    Caroline Peyrode, Valérie Weber, Aurélien Vidal, Philippe Auzeloux, Sophie Besse, Jean Michel Chezal & Elisabeth Miot-Noirault

  2. UMR S957 Inserm, Nantes Atlantique Université, 44035, Nantes, France

    Emmanuelle David, François Gouin, Dominique Heymann & François Rédini

  3. CLCC Jean Perrin, 63001, Clermont-Ferrand, France

    Yves Communal & Marie Mélanie Dauplat

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  1. Caroline Peyrode
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  2. Valérie Weber
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  3. Emmanuelle David
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  4. Aurélien Vidal
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  5. Philippe Auzeloux
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  6. Yves Communal
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  7. Marie Mélanie Dauplat
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  8. Sophie Besse
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  9. François Gouin
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  10. Dominique Heymann
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  11. Jean Michel Chezal
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  13. Elisabeth Miot-Noirault
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Correspondence to Caroline Peyrode.

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Peyrode, C., Weber, V., David, E. et al. Quaternary ammonium-melphalan conjugate for anticancer therapy of chondrosarcoma: in vitro and in vivo preclinical studies. Invest New Drugs 30, 1782–1790 (2012). https://doi.org/10.1007/s10637-011-9663-z

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  • DOI: https://doi.org/10.1007/s10637-011-9663-z

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