Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

Valentina Zuco , Rosanna Supino , Enrica Favini , Monica Tortoreto , Raffaella Cincinelli , Anna Cleta Croce , Federica Bucci , Claudio Pisano , Franco Zunino

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 down-regulation 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 was 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.

Mots clés: Camptothecin; ST1968; Topotecan; Drug resistance

Valentina Zuco, Rosanna Supino, Enrica Favini, Monica Tortoreto, Raffaella Cincinelli, et al.. Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma. Biochemical Pharmacology, 2009, 79 (4), pp.535. ⟨10.1016/j.bcp.2009.09.012⟩. ⟨hal-00544815⟩