Valoti G, Nicoletti M I, Pellegrino A, Jimeno J, Hendriks H, D'Incalci M, Faircloth G, Giavazzi R
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Clin Cancer Res. 1998 Aug;4(8):1977-83.
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.
新型海洋天然产物埃博霉素（ET）-743的抗肿瘤活性，针对一组在裸鼠中表现出不同恶性行为和药物反应性的人卵巢癌异种移植瘤进行了评估。这些肿瘤模型包括三个皮下移植到裸鼠体内的异种移植瘤（HOC18、HOC22-S和MNB-PTX-1），代表对顺铂（DDP）不同程度的敏感性，顺铂用作卵巢癌的参考药物，另外还有两个异种移植瘤（HOC22和HOC8），它们在裸鼠腹腔内具有高度恶性，代表了这种肿瘤的生长模式。在最大耐受剂量0.2mg/kg下，采用每4天静脉注射一次的间歇给药方案，ET-743对HOC22-S（对DDP敏感）具有高度活性，可诱导持久的完全消退，对HOC18（对DDP轻度敏感）也有活性，可诱导部分肿瘤消退。此外，在携带晚期HOC18肿瘤（肿瘤重量400mg；对DDP无反应）的小鼠中观察到显著的生长延迟。然而，ET-743对MNB-PTX-1无效，MNB-PTX-1是一种对包括DDP在内的化疗高度耐药的肿瘤。在腹腔内卵巢癌异种移植模型中，最大耐受剂量的ET-743可使所有携带HOC22肿瘤的小鼠肿瘤完全缓解，其中25%经组织病理学证实治愈，对HOC8产生轻微的肿瘤生长延迟。这些结果表明，ET-743是一种针对卵巢癌异种移植瘤的有效药物，在同一肿瘤模型中与DDP具有同等活性或更有效。我们对人卵巢癌异种移植瘤的研究结果证明了对该药物针对此肿瘤靶点进行临床评估的合理性。
