melphalan and Chondrosarcoma

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.

Topics: Animals; Antineoplastic Agents, Alkylating; Bone Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Chondrosarcoma; Drug Screening Assays, Antitumor; Heterocyclic Compounds, 1-Ring; Humans; Male; Melphalan; Proteoglycans; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley

To enhance affinity for malignant cartilaginous tumors (chondrosarcomas), quaternary ammonium (QA) conjugates of chlorambucil and melphalan were prepared by linking the QA moiety to nitrogen mustards via an amide bond. They exhibited closely similar and sometimes more favorable values than their parent compounds. In the cell lines tested, the two QA conjugates displayed appreciable cytotoxicity, the QA conjugate of chlorambucil even showing an enhanced efficiency against chondrosarcoma compared with chlorambucil.

Topics: Animals; Antineoplastic Agents; Chlorambucil; Chondrosarcoma; Drug Screening Assays, Antitumor; Humans; Melanoma; Melphalan; Mice; Quaternary Ammonium Compounds; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Stem Cell Assay

Topics: Adolescent; Bone Neoplasms; Child; Child, Preschool; Chondrosarcoma; Cyclophosphamide; Humans; Infant; Lymphoma, Large B-Cell, Diffuse; Melphalan; Methotrexate; Sarcoma, Ewing

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Child; Chondrosarcoma; Female; Humans; Hypothermia, Induced; Hypoxia; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methods; Osteosarcoma; Radiation Injuries; Tourniquets

Topics: Adolescent; Amputation, Surgical; Anti-Bacterial Agents; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Child; Chondrosarcoma; Giant Cell Tumors; Hip; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Neoplasm Metastasis; Osteosarcoma; Radioisotopes; Sarcoma, Ewing; Shoulder; Vitamins

Topics: Adolescent; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Child; Chondrosarcoma; Dogs; Femur; Fibula; Hemangiosarcoma; Humans; Melanoma; Melphalan; Mesenchymoma; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Sarcoma; Sarcoma, Ewing; Ulna; Uracil

Topics: Aorta; Aorta, Abdominal; Bone Neoplasms; Carotid Arteries; Chemotherapy, Cancer, Regional Perfusion; Chondrosarcoma; Dactinomycin; Dogs; Fibrosarcoma; Iliac Artery; Iliac Vein; Leiomyosarcoma; Liposarcoma; Lymphoma, Non-Hodgkin; Melphalan; Mesothelioma; Neoplasms; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Kaposi; Subclavian Artery; Vena Cava, Inferior