title: Quaternary ammonium-melphalan conjugate for anticancer therapy of chondrosarcoma: in vitro and in vivo preclinical studies.
abstract: 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 (99m)Tc-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.
authors.affiliation: UMR 990 INSERM/ UdA, Université d'Auvergne, Rue Montalembert, BP184, 63005 Clermont Ferrand Cedex, France. caroline.peyrode@inserm.fr
authors.forename: Caroline
authors.initials: C
authors.lastname: Peyrode
authors.forename: Valérie
authors.initials: V
authors.lastname: Weber
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: David
authors.forename: Aurélien
authors.initials: A
authors.lastname: Vidal
authors.forename: Philippe
authors.initials: P
authors.lastname: Auzeloux
authors.forename: Yves
authors.initials: Y
authors.lastname: Communal
authors.forename: Marie Mélanie
authors.initials: MM
authors.lastname: Dauplat
authors.forename: Sophie
authors.initials: S
authors.lastname: Besse
authors.forename: François
authors.initials: F
authors.lastname: Gouin
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Chezal
authors.forename: François
authors.initials: F
authors.lastname: Rédini
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Miot-Noirault
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002813:Chondrosarcoma / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D008297:Male; D008558:Melphalan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011509:Proteoglycans / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006573:Heterocyclic Compounds, 1-Ring; C407019:N-(triethylammonium)-3-propyl(15)ane-N5; D011509:Proteoglycans; D000644:Quaternary Ammonium Compounds; D008558:Melphalan