IDN 5390: an oral taxane candidate for protracted treatment schedules

Abstract

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always 485%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg À1 . In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD ¼ 10 mg kg À1 ). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure

“…Their susceptibility to resistance development has been attributed to a 0.01% subpopulation of mismatch repair defective A2780 cells (McLaughlin et al, 1991;Aquilina et al, 2000). A2780 sub-lines have been derived with resistance to many chemotherapeutic compounds including cisplatin (Behrens et al, 1987), taxol (Ferlini et al, 2003), both cisplatin and taxol (Pratesi et al, 2003) and DOX (Hamilton et al, 1984). STX140-resistant sub-lines could not be derived from MCF-7, PC-3 and LNCaP cells, all which have similar sensitivities to STX140 as A2780 cells.…”

Antitumour and antiangiogenic effects of IDN 5390, a novel C-seco taxane, in a paclitaxel-resistant human ovarian tumour xenograft

“…For in vitro studies, drugs were dissolved in dimethylsulphoxide (DMSO) at 2 mg ml À1 and diluted in culture medium (DMSO final concentration 0.25%). For in vivo studies, PTX was dissolved by adding absolute ethanol and Cremophor ELP (both 5% of the final volume) , whereas IDN 5390, dissolved in Polysorbate 80, was diluted just before use by adding 0.9% NaCl to the final concentration of 10% v v À1 (Pratesi et al, 2003). The study was performed on the A2780 human ovarian carcinoma cell line and two variants, that is, the A2780/DDP cell subline, selected in vitro for resistance to cisplatin (Beherens et al, 1987), and the INT.ACP/PTX cell subline.…”

“…Bcl-2 expression was examined in whole-cell extracts prepared as previously reported in Pratesi et al (2003). Briefly, equal amounts of proteins were separated by SDS -PAGE and transferred onto nitrocellulose sheets.…”

“…The novel C-seco taxane IDN 5390, which is currently under study in preclinical systems, was originally selected for its potent antimotility activity and low cytotoxicity in endothelial cells (Taraboletti et al, 2002). In vivo studies in human tumour xenografts have indicated a unique profile of tolerability and antitumour activity for IDN 5390 when administered by a daily schedule for a prolonged time (Pratesi et al, 2003).…”

“…Conventional antitumour drugs delivered according to the so-called 'metronomic chemotherapy' were effective even against drug-resistant tumours (Browder et al, 2000;Fidler and Ellis, 2000). When administered according to a frequent and prolonged schedule, IDN 5390 is active against all human tumour xenografts investigated, including the PTXresistant ones (Pratesi et al, 2003).…”