De Cesare Michelandrea, Pratesi Graziella, Veneroni Silvia, Bergottini Raffaella, Zunino Franco
Istituto Nazionale Tumori, Milan, Italy.
Clin Cancer Res. 2004 Nov 1;10(21):7357-64. doi: 10.1158/1078-0432.CCR-04-0962.
Gimatecan, a novel oral lipophilic camptothecin characterized by favorable features at molecular/cellular level and by a promising profile of preclinical activity, is currently in clinical phase I/II. The aim of the study was to additionally investigate the therapeutic potential of the drug in human tumor xenografts growing in different organs as models representative of tumor growth in the clinical setting.
The models include two orthotopic central nervous system tumors, two melanomas growing intracranially, and an ovarian carcinoma growing i.p. In addition, gimatecan was tested against experimental lung metastases of two tumor types (lung and ovarian carcinomas). Gimatecan was delivered by oral gavage according to various schedules (daily or intermittent). The time (in days) mice required to show evident signs of disease was used as end point for drug efficacy.
Gimatecan was highly effective in delaying disease manifestations in all tumor systems investigated. In the intracranially growing tumors, a significant time increase (versus control mice) was achieved by the drug administered according to all of the schedules. In addition, almost all treated mice were alive and tumor-free at the end of the experiment in the metastatic models and in the ascitic ovarian tumor. The daily prolonged treatment schedule was the best one.
In all tumor systems investigated, including orthotopic tumor growth models and lung metastases, the oral administration of gimatecan showed a therapeutic benefit in terms of survival increase. The good oral availability allowed a prolonged daily treatment regimen, which seems the most promising to exploit the therapeutic potential of the drug.
吉美替康是一种新型口服亲脂性喜树碱，在分子/细胞水平具有良好特性且临床前活性表现良好，目前处于临床I/II期。本研究的目的是进一步研究该药物在不同器官中生长的人肿瘤异种移植模型中的治疗潜力，这些模型代表了临床环境中的肿瘤生长情况。
这些模型包括两种原位中枢神经系统肿瘤、两种颅内生长的黑色素瘤以及一种腹腔内生长的卵巢癌。此外，还对吉美替康针对两种肿瘤类型（肺癌和卵巢癌）的实验性肺转移进行了测试。吉美替康按照不同给药方案（每日或间歇给药）通过灌胃给药。将小鼠出现明显疾病迹象所需的时间（以天为单位）用作药物疗效的终点。
在所有研究的肿瘤系统中，吉美替康在延迟疾病表现方面非常有效。在颅内生长的肿瘤中，按照所有给药方案给药的药物均使疾病出现时间显著延长（与对照小鼠相比）。此外，在转移性模型和腹水型卵巢肿瘤中，几乎所有接受治疗的小鼠在实验结束时均存活且无肿瘤。每日延长给药方案是最佳方案。
在所有研究的肿瘤系统中，包括原位肿瘤生长模型和肺转移模型，口服吉美替康在提高生存率方面显示出治疗益处。良好的口服生物利用度使得可以采用每日延长给药方案，这似乎是发挥该药物治疗潜力最有前景的方式。
