ENHANCED SENSITIVITY OF SOFT TISSUE SARCOMA TO TRAIL MEDIATED APOPTOSIS

Abstract

TRAIL/Apo2L is a member of the tumour necrosis factor (TNF) family of cytokines that induces death of cancer cells but not normal cells. Its potent apoptotic activity is mediated through its cell surface death domain containing receptors, DR4 and DR5. TRAIL binds also to three “decoy” receptors, DcR1, DcR2 and osteoprotegerin (OPG), which lack functional death domains, and do not induce apoptosis. The aim of this study was to investigate the cytotoxic activity of TRAIL as a single agent or in combination with clinically relevant anti-sarcoma drugs on human soft tissue sarcomas that are traditionally resistant to chemotherapy. Human soft tissue sarcomas known to be resistant to chemotherapy were taken at the time of biopsy and cultured to produce a cell line. This cell line was then tested against TRAIL, standard chemotherapeutic agents (including doxorubicin, cis platinum, etoposide, methotrexate and cyclophosphamide) and in combination. When used alone, TRAIL and/or the standard chemotherapeutic agents produced minimal tumour necrosis and this was mirrored in the clinical results. In combination, however, up to 60% necrosis was seen, with doxorubicin the most effective chemotherapeutic agent used. These results indicate that chemotherapy and TRAIL act synergistically to kill sarcoma cells and potentially opens up a new area of cytotoxic treatment for these difficult malignancies.