Homocamptothecins (hCPTs) represent a new generation of
antitumor agents targeting
DNA topoisomerase I. The expanded seven-membered
lactone E-ring that characterizes hCPTs enhances the plasma stability of the
drug and reinforces the inhibition of
topoisomerase I compared with conventional six-membered CPTs. hCPTs are more efficient than the CPTs at promoting cleavage at T/G sites and induce additional cleavage at C/G sites. Compound BN80765 and its difluoro analogue
diflomotecan (DN80915) are potent
cytotoxic agents and efficiently induce apoptosis in
tumor cells. They display strong antiproliferative activities against specific
tumor types.
Diflomotecan is remarkably efficient at inhibiting the growth of human
colon cancer cells in vivo and, administered orally, it also shows superior activities against human
prostate cancers compared with the benchmark products
topotecan (
TPT) and
irinotecan (IRT).
Diflomotecan has entered phase I clinical testing and antitumor activity has been observed in patients. This 9,10-difluoro-hCPTs derivative is one of the most promising new members of the 'tecan' family. This review summarizes the recent discoveries in the
topoisomerase I field and presents the different
camptothecin (
CPT) analogues currently evaluated as
anticancer agents. The specific properties of hCPTs are highlighted.