Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts.
The antitumor activity of ecteinascidin (ET)-743, a novel marine natural product, was evaluated against a panel of human ovarian carcinoma xenografts characterized by different malignant behaviors and drug responsiveness in nude mice. These tumor models included three xenografts transplanted s.c. (HOC18, HOC22-S, and MNB-PTX-1) into nude mice, representing different levels of sensitivity to cisplatinum (DDP), which was used as reference drug for ovarian carcinoma, and two other xenografts (HOC22 and HOC8), which are highly malignant in the peritoneal cavity of nude mice, representing the growth pattern of this neoplasm. At the maximum tolerated dose of 0.2 mg/kg using an intermittent schedule of one i.v. injection every 4 days, ET-743 was highly active against HOC22-S (sensitive to DDP), inducing long-lasting, complete regressions, and against HOC18 (marginally sensitive to DDP), inducing partial tumor regressions. Moreover, significant growth delay was observed in mice bearing late-stage HOC18 tumor (400-mg tumor weight; nonresponsive to DDP). ET-743, however, was not active against MNB-PTX-1, a tumor that is highly resistant to chemotherapy, including DDP. In the i.p. ovarian carcinoma xenograft model, ET-743 at the maximum tolerated dose induced complete tumor remissions in all mice bearing HOC22 tumor, with 25% histopathologically confirmed cures, and produced marginal tumor growth delay against HOC8. These results indicate that ET-743 is a potent drug against ovarian carcinoma xenografts, being equally as active or more efficacious than DDP in the same tumor line. Our findings with human ovarian carcinoma xenografts justify clinical assessment of this drug with this tumor target.
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
G
G
Valoti
M I
MI
Nicoletti
A
A
Pellegrino
J
J
Jimeno
H
H
Hendriks
M
M
D'Incalci
G
G
Faircloth
R
R
Giavazzi
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010529:Peritoneal Cavity / Q000473:pathology; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin