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IDN 5390: an oral taxane candidate for protracted treatment schedules
G Pratesi1, D Laccabue, C Lanzi
1Istituto Nazionale Tumori, via Venezian I, Milano, Italy. graziella.pratesi@istitutotumori.mi.it
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 >85%) 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(-1). In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD=10 mg kg(-1)). 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.
Insights
IDN 5390, a novel C-seco taxane, shows potent anti-tumor activity and high tolerability in preclinical models. Its oral efficacy and favorable safety profile make it promising for exploiting taxanes' antiangiogenic potential.
Area of Science:
- Oncology
- Pharmacology
Background:
- Taxanes exhibit antiangiogenic properties, suggesting therapeutic potential with prolonged low-dose exposure targeting endothelial cells.
- Developing taxanes with improved tolerability is crucial for exploiting their antiangiogenic effects in protracted treatment schedules.
Purpose of the Study:
- To evaluate the preclinical pharmacologic profile of IDN 5390, a novel C-seco taxane, in various human tumor xenografts.
- To compare the efficacy and toxicity of IDN 5390 with paclitaxel in protracted treatment schedules.
Main Methods:
- IDN 5390 was administered via subcutaneous injection daily for 5 days per week in ovarian, colon, and glioblastoma xenografts.
- Maximum tolerated dose (MTD) and tumor growth inhibition were assessed for IDN 5390 and paclitaxel.
- Oral bioavailability and efficacy of IDN 5390 were investigated in human tumor xenografts.
Main Results:
- IDN 5390 demonstrated high efficacy (>85% tumor growth inhibition) at well-tolerated doses (MTD=120 mg/kg) with no local toxicity.
- Paclitaxel showed variable efficacy and significant local toxicity (MTD=10 mg/kg) under the same schedule.
- Oral IDN 5390 exhibited good bioavailability and maintained substantial efficacy, including against paclitaxel-resistant tumors.
Conclusions:
- IDN 5390 offers significant therapeutic advantages over paclitaxel in protracted daily treatment due to its oral efficacy and high tolerability.
- These features position IDN 5390 favorably for exploiting antiangiogenic potential and for combination therapies.