Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of ecteinascidin-743 as a potent cytotoxic agent.
The cytotoxic effects of ecteinascidin-743(ET-743), a novel marine natural product, were evaluated and compared with that of clinically used anticancer agents methotrexate, doxorubicin, etoposide, and paclitaxel in eight human soft tissue sarcoma (STS) cell lines. HT-1080, a fibrosarcoma cell line, and HS-42, a malignant mesodermal cell line, were the most sensitive of the cell lines to methotrexate, doxorubicin, etoposide, and paclitaxel. Other cell lines (IC50s) varied considerably and were more resistant to these agents. ET-743 was more potent than any of these agents, with IC50s in the pM range in all of the cell lines. Cytotoxicity of ET-743 was dose- and time-related (4-72 h exposure). Cytotoxic concentrations of ET-743 produced a S/G2 block in all of the cell lines tested. Three colon adenocarcinoma cell lines, HCT-8, HT-29, and HCT-116, and one breast cancer cell line, MCF-7, were 1-2 logs less sensitive to ET-743 than the STS cell lines. Cell lines were also characterized as to expression of oncogenes and tumor suppressor genes to attempt to correlate sensitivity of these cell lines to ET-743 and other chemotherapeutic agents. All of the cell lines except M8805, a malignant fibrous histiocytoma cell line, had mutations in p53 and/or overexpressed the MDM2 protein. Only HS-18, a liposarcoma cell line, lacked expression of the retinoblastoma protein. None of the cell lines had detectable expression of P-glycoprotein as measured by immunohistochemistry. ET-743 is an extremely potent cytotoxic agent against human STS cell lines and is being evaluated as an antitumor agent in this disease.
Li
W W
WW
Laboratories of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Takahashi
N
N
Jhanwar
S
S
Cordon-Cardo
C
C
Elisseyeff
Y
Y
Jimeno
J
J
Faircloth
G
G
Bertino
J R
JR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology*; D008727:Methotrexate / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D012680:Sensitivity and Specificity; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004149:Dioxoles; D007546:Isoquinolines; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; D000077606:Trabectedin; D008727:Methotrexate