Pratesi Graziella, De Cesare Michelandrea, Carenini Nives, Perego Paola, Righetti Sabina C, Cucco Carla, Merlini Lucio, Pisano Claudio, Penco Sergio, Carminati Paolo, Vesci Loredana, Zunino Franco
Istituto Nazionale Tumori, 20133 Milan, Italy.
Clin Cancer Res. 2002 Dec;8(12):3904-9.
ST1481 is the lead compound of a novel series of 7-modified camptothecins, the 7-oxyimino methyl derivatives, characterized by potent topoisomerase I inhibition and cytotoxic activity. Based on its therapeutic efficacy in a human non-small cell lung carcinoma model and its favorable pharmacological profile, the novel analogue was selected for further preclinical development.
We investigated the growth-inhibitory effects of ST1481 and topotecan, used as a reference compound, in a panel of human tumor cell lines of various tumor types (ovarian carcinoma, glioblastoma, osteosarcoma, and melanoma), including sublines with acquired resistance to cisplatin. We explored the antitumor efficacy in a large panel of human tumor xenografts, with particular reference to intrinsically resistant tumor types, using oral administration and an intermittent treatment schedule.
ST1481 showed a potent antiproliferative activity with comparable effects in all tested cell lines. Only U-87-MG glioma cells were less sensitive, presumably as a consequence of the efficiency of the S-phase checkpoint. ST1481 produced a remarkable antitumor effect (tumor volume inhibition > 85%) in 16 of 18 examined models, with an appreciable rate of complete tumor regressions in 11 of 18 models (despite the nonoptimal intermittent treatment schedule). The most impressive antitumor effects were observed against lung carcinoma, melanoma, and osteosarcoma models, as documented by the high rate of complete responses (up to 100%). The efficacy of ST1481 was significantly superior to that of topotecan in 9 of 17 tumors. The novel drug was also markedly effective against slowly growing tumors (A549 lung carcinoma and HT29 colon carcinoma) when a daily protracted treatment was used to fully exploit the therapeutic potential of camptothecins.
The unusual potency of ST1481 in a variety of tumor cell lines suggests the ability of the drug to overcome several resistance factors. The profile of antitumor efficacy further supports the therapeutic interest in the novel analogue and provides a rational basis for clinical evaluation in selected tumor types.
ST1481是新型7-修饰喜树碱系列的先导化合物，即7-氧亚氨基甲基衍生物，其特点是具有强大的拓扑异构酶I抑制作用和细胞毒性活性。基于其在人非小细胞肺癌模型中的治疗效果及其良好的药理学特性，选择该新型类似物进行进一步的临床前开发。
我们研究了ST1481和作为参考化合物的拓扑替康对一系列不同肿瘤类型（卵巢癌、胶质母细胞瘤、骨肉瘤和黑色素瘤）的人肿瘤细胞系的生长抑制作用，包括对顺铂获得性耐药的亚系。我们使用口服给药和间歇治疗方案，在大量人肿瘤异种移植模型中探索了抗肿瘤疗效，特别关注固有耐药的肿瘤类型。
ST1481在所有测试细胞系中均显示出强大的抗增殖活性，效果相当。只有U-87-MG胶质瘤细胞不太敏感，可能是由于S期检查点的效率。在18个检测模型中的16个中，ST1481产生了显著的抗肿瘤效果（肿瘤体积抑制>85%），在18个模型中的11个中出现了可观的肿瘤完全消退率（尽管治疗方案不是最佳的间歇方案）。在肺癌、黑色素瘤和骨肉瘤模型中观察到了最令人印象深刻的抗肿瘤效果，完全缓解率很高（高达100%）。在17个肿瘤中的9个中，ST1481的疗效显著优于拓扑替康。当采用每日延长治疗以充分发挥喜树碱的治疗潜力时，这种新药对生长缓慢的肿瘤（A549肺癌和HT29结肠癌）也有明显效果。
ST1481在多种肿瘤细胞系中具有非凡的效力，表明该药物有能力克服多种耐药因素。抗肿瘤疗效概况进一步支持了对该新型类似物的治疗兴趣，并为在选定肿瘤类型中进行临床评估提供了合理依据。
