Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells

Ecteinascidin 743 (ET-743) is a potent antitumor agent from the Caribbean t unicate Ecteinascidin turbinata and is presently in clinical trials for hum an cancers. To better understand how ET-743 might be used clinically, the p resent study used SRB assays to examine the cytotoxicity resulting from com bining ET-743 with three other antineoplastic agents: doxorubicin (DXR), tr imetrexate, and paclitaxel in different administration schedules in two sof t tissue sarcoma cell lines, HT-1080 and HS-18, in vitro. Concurrent exposu re of ET-743 with DXR resulted in synergistic interactions in both cell lin es. Addition of ET-743 for 24 h before DXR was the most effective cytotoxic regimen against both cell lines. Morphological study by fluorescence micro scopy revealed that combination treatment of both cells with ET-743 and DXR induced apoptosis. Exposure to paclitaxel before ET-743 was also an effect ive regimen. These results encourage studies of the combination of ET-743 a nd DXR in the treatment of soft tissue sarcoma, because each of these agent s have activity in this disease.