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

Abstract

IDN 5390 is a novel C-seco taxane analogue selected for preclinical development on the basis of its antimotility activity on endothelial cells, antitumour efficacy in a large panel of human tumour xenografts and high tolerability in mouse. On the basis of oral availability, IDN 5390 is suitable for protracted administration schedules. Such a treatment schedule has been reported as the most appropriate to exploit the antiangiogenic effects of cytotoxic drugs. An ability to downregulate angiogenesis-related growth factors in tumour cells has been described for IDN 5390. The aim of the study was to investigate the antitumour and antiangiogenic potential of oral IDN 5390 on a human ovarian carcinoma xenograft, the INT.ACP/PTX, resistant to paclitaxel (PTX). Such tumour line was derived in vivo from a cisplatin-resistant tumour line, the A2780/DDP, which is sensitive to PTX. Compared to the parental cells, INT.ACP/PTX cells exhibited a high level of Pgp expression, resulting in a reduced in vitro sensitivity to both PTX and IDN 5390. The INT.ACP/PTX tumour xenograft was still resistant to PTX, but responsive to IDN 5390, when delivered per os, by a daily prolonged schedule. A direct effect on tumour cells, allowed by the high tolerability of the compound in mouse, cannot be excluded in vivo. Immunohistochemical analysis indicated a significant reduction of microvessel density in IDN 5390-treated tumours, lasting till 7 days after the last drug administration. Thus, a prolonged inhibitory effect on tumour angiogenesis is consistent with the persistent growth control of INT.ACP/PTX tumour achieved by IDN 5390. On the contrary, the low tolerability and the limited oral availability of conventional taxanes do not allow an easy feasibility of such treatment regimen. Thus, the tolerability profile of IDN 5390 in preclinical systems and its efficacy in PTX-resistant tumours support the therapeutic interest for its clinical development, with particular attention to oral daily prolonged schedules.

Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature:Implications for Cancer Treatment

“…However, the use of MTAs with a true metronomic dosing administration still remains limited, partly because of the lack of available oral formulations. Nevertheless this obstacle may be overcome, for instance, with the development of new MTAs such as the second generation of taxanes that can be orally given [211].…”

The Seco-Taxane IDN5390 Is Able to Target Class III β-Tubulin and to Overcome Paclitaxel Resistance

“…This compound originally selected for its ability to affect endothelial cell motility (8) has a favorable bioavailability, is well tolerated, and shows a significant antineoplastic activity on a panel of different tumor models, including paclitaxel-resistant tumors (9,10). In this study, the role of class III h-tubulin as a possible mechanism underlying the unique pharmacodynamic profile of IDN5390 in paclitaxelresistant cells has been explored.…”

Pharmacokinetics and Metabolism in Mice of IDN 5390 (13-(N-Boc-3-i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III), a New Oral C-seco-Taxane Derivative with Antiangiogenic Property Effective on Paclitaxel-Resistant Tumors

“…Initially, IDN 5390 was selected for its ability to inhibit endothelial cell motility from a screening of paclitaxel analogs with antiangiogenic properties (Taraboletti et al, 2003). This antiangiogenic effect was confirmed in a paclitaxel-resistant tumor model (Petrangolini et al, 2004). Moreover, the compound has high antitumor activity in paclitaxel-resistant cells over-expressing class III ␤-tubulin.…”

“…IDN 5390 showed high activity against a variety of human tumor xenografts, both sensitive and resistant to paclitaxel, including ovarian and colon carcinoma and glioblastoma (Taraboletti et al, 2002;Petrangolini et al, 2004). The optimal schedule for antitumor activity requires protracted administration of subcutaneous or oral doses (Taraboletti et al, 2002;Pratesi et al, 2003).…”