ST1968 (
namitecan), a novel 7-modified hydrophilic
camptothecin, was found to be effective against
tumor models relatively resistant to
topotecan and
irinotecan. Based on this observation, this study was designed to investigate the cellular and antitumor effects of
ST1968 in a subline of A431,
squamous cell carcinoma, selected for resistance to
topotecan (A431/
TPT). This model was characterized by a slow growth rate, associated with downregulation of EGFR and
topoisomerase I. In contrast to other camptothecins (SN38 and
gimatecan),
ST1968 was able to overcome almost completely the resistance at cellular level. The cellular pharmacokinetics indicated a comparable accumulation and retention of
ST1968 in sensitive and resistant cells, in spite of expression of the efflux transporter,
P-glycoprotein, in resistant cells. The uptake and retention of
topotecan were dramatically reduced in both tumor cell lines, but more evident in the resistant one. In contrast to
topotecan,
ST1968 retained an outstanding efficacy in vivo against the resistant
tumor (A431/
TPT). The results are consistent with the interpretation that
ST1968 was able to overcome the most relevant mechanisms associated with the development of
topotecan resistance (i.e., slow proliferation and target downregulation) owing to its peculiar pharmacokinetic behaviour.