Potent antitumor activity and improved pharmacological profile of ST1481, a novel 7-substituted camptothecin

Relevant drawbacks of the molecular structure and mechanism of the action o f camptothecins are the instability of the E ring lactone and the reversibi lity of drug-target interaction. Such features are expected to limit the cl inical efficacy of conventional camptothecins. In an attempt to overcome th ese limitations and to improve the pharmacological profile of camptothecins , a novel series of seven modified lipophilic analogues was synthesized bas ed on the hypothesis that lipophilicity could promote a rapid cellular accu mulation and stabilization of drug-tar,get interaction. A novel analogue (S T1481) of the series, characterized by a potent antitopoisomerase and cytot oxic activity, was selected for preclinical development. A detailed preclin ical study of ST1481 was performed in the H460 non-small cell lung tumor mo del using oral administration and various treatment schedules. Under all of the conditions, ST1481 exhibited an impressive efficacy in terms of tumor growth inhibition (tumor volume inhibition percentage >99%), log(10) cell k ill, rate of complete responses (including "cures"), and an improvement of the therapeutic index compared with topotecan (used as the reference drug). The cytotoxic potency was also reflected by the in vivo potency, because t he drug activity was observed at doses as low as 0.25 mg/kg with the daily schedule. In contrast to topotecan, no cross-resistance to ST1481 was found in ovarian carcinoma cells overexpressing P-glycoprotein (A2780/DX). A sim ilar trend in the improvement of activity was also observed in the same tum or model growing in vivo with a 100% rate of complete tumor regressions. A rapid intestinal absorption and good oral bioavailability were supported by in vivo distribution studies, because the peak values of drug accumulation were found from 1 to 2 h after administration. The relevant liver accumula tion may account for a marked effect of ST1481 against liver metastases ind uced by the ovarian carcinoma IGROV-1. In conclusion, the results support t he hypothesis that a potent lipophilic camptothecin with a proper substitue nt at the position 7 may have therapeutic advantages likely related to a ra pid intracellular uptake and tissue distribution, stabilization of the drug -target complex, and good oral bioavailability. Overall, the results suppor t the preclinical interest of ST1481 in terms of efficacy, potency, toxicit y profile, and ability to overcome multidrug resistance.