AbstractOsteosarcoma is one of the most common primary malignant tumors of bone. Treatment of this tumor with systemic chemotherapy dramatically improves the prognosis, although the molecular mechanisms involved in the drug action are poorly understood. In chemosensitive leukaemic T cells and certain solid tumors. cytotoxic drugs mediate the induction of apoptosis by activation of the CD95/APO‐1/Fas system. Triggering of the corresponding signaling pathway may involve CD95‐receptor/ligand interaction, activation of caspases, or alterations in mitochondrial function. The purpose of our study was to determine if similar mechanisms are involved in the chemosensitivity of osteosarcomas. We found that cytotoxic drugs induce characteristic biochemical and morphological alterations related to apoptosis in osteosarcoma cell lines, including activation of caspases and disturbance of mitochondrial function. However, drug treatment did not result in activation of CD95‐receptor or CD95‐ligand mRNA. In addition, drug‐induced apoptosis was blocked by caspase inhibitors but not by inhibition of CD95‐ligand action, indicating a CD95‐receptor/ligand‐independent mechanism in osteosar