The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison

BN 80915, a lead compound of the homocamptothecin (hCPT) family, has entere d 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 spi te of the modification to the crucial E-ring of CPTs, BN 80915 retains topo isomerase 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 IC (50)s values consistently lower than those of SN38 in sensitive cell lines as well as in their related multidrug-resistant lines overexpressing P-glyc oprotein or multidrug resistance-associated protein. Furthermore, in human plasma, in contrast to CPT analogs, the hydrolysis of BN 80915 is slow, lea ding to improved plasma stability, and irreversible, thus avoiding toxicity related to the accumulation of active principle during excretion in the ur inary tract. These findings may account for the good in vivo efficacy obser ved in PC3 xenograft experiments where BN 80915 administered orally at very low doses doubled the tumor growth delay In comparison to CPT-11 administe red i,p, Altogether, these results strongly support further development of BN 80915, [(C) 2001 Lippincott Williams & Wilkins.].