BN 80915, a lead compound of the homocamptothecin (hCPT) family, has entered clinical trials. BN 80915 is a difluoro-hCPT where the six-membered alpha-hydroxylactone ring of camptothecin (CPT) is replaced by a seven-membered beta-hydroxylactone ring. Preclinical data reported here show that in spite of the modification to the crucial E-ring of CPTs, BN 80915 retains topoisomerase I poisoning activity as shown in living HT29 cells as well as in cell-free assays, where BN 80915 always performs better than SN-38 or TPT. In antiproliferative assays BN 80915 is also very potent as evidenced by IC50s values consistently lower than those of SN38 in sensitive cell lines as well as in their related multidrug-resistant lines overexpressing P-glycoprotein or multidrug resistance-associated protein. Furthermore, in human plasma, in contrast to CPT analogs, the hydrolysis of BN 80915 is slow, leading to improved plasma stability, and irreversible, thus avoiding toxicity related to the accumulation of active principle during excretion in the urinary tract. These findings may account for the good in vivo efficacy observed in PC3 xenograft experiments where BN 80915 administered orally at very low doses doubled the tumor growth delay in comparison to CPT-11 administered i.p. Altogether, these results strongly support further development of BN 80915.

中文翻译：

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同型喜树碱BN 80915是一种高效口服活性拓扑异构酶I毒药。

同型喜树碱（hCPT）家族的先导化合物BN 80915已进入临床试验。BN 80915是二氟-hCPT，其中喜树碱（CPT）的六元α-羟基内酯环被七元的β-羟基内酯环取代。此处报道的临床前数据表明，尽管对CPT的关键E环进行了修饰，但BN 80915仍保留了拓扑异构酶I的中毒活性，这在活HT29细胞以及无细胞试验中均显示，其中BN 80915的性能始终优于SN -38或TPT。在抗增殖试验中，BN 80915的效价也很强，IC50s值始终低于敏感细胞系及其过表达P-糖蛋白或与多药耐药相关蛋白的相关多药耐药株中SN38的值。此外，在人体血浆中，与CPT类似物相比，BN 80915的水解缓慢，导致血浆稳定性提高，并且不可逆，因此避免了与尿道排泄过程中有效成分的积累有关的毒性。这些发现可能解释了在PC3异种移植实验中观察到的良好体内功效，其中以非常低的剂量口服施用的BN 80915与通过ip施用的CPT-11相比，使肿瘤生长延迟增加了一倍，这些结果有力地支持了BN 80915的进一步发展。