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 tunicate Ecteinascidin turbinata and is presently in clinical trials for human cancers. To better understand how ET-743 might be used clinically, the present study used SRB assays to examine the cytotoxicity resulting from combining ET-743 with three other antineoplastic agents: doxorubicin (DXR), trimetrexate, and paclitaxel in different administration schedules in two soft tissue sarcoma cell lines, HT-1080 and HS-18, in vitro. Concurrent exposure of ET-743 with DXR resulted in synergistic interactions in both cell lines. Addition of ET-743 for 24 h before DXR was the most effective cytotoxic regimen against both cell lines. Morphological study by fluorescence microscopy revealed that combination treatment of both cells with ET-743 and DXR induced apoptosis. Exposure to paclitaxel before ET-743 was also an effective regimen. These results encourage studies of the combination of ET-743 and DXR in the treatment of soft tissue sarcoma, because each of these agents have activity in this disease.
Takahashi
N
N
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Li
W W
WW
Banerjee
D
D
Scotto
K W
KW
Bertino
J R
JR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D004149:Dioxoles / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000494:pharmacology*; D012509:Sarcoma / Q000188:drug therapy / Q000473:pathology; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D016597:Trimetrexate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D000077606:Trabectedin; D017239:Paclitaxel; D016597:Trimetrexate