title: Evaluation of the pharmacokinetic properties of new taxane derivatives
Creators: name: Marangon, Elena
Publisher: name: The Open University
Year: 2010

description: Taxanes represent a very important class of anticancer agents available for clinical use since 1990s. Currently, two taxanes, paclitaxel and docetaxel, are included in multi drug regimens for the therapy of several solid tumours, such as ovary, breast, head and neck, prostate and non-small cell lung cancers. Taxanes act by inhibiting microtubule dynamics, thereby blocking cell cycle and activating cell death. Despite the relevant contribution of taxanes in improving the overall survival and the quality of life of cancer patients, there are some limitations in the therapeutic use of these drugs that have driven research for new analogues having an enlarged antitumour activity profile, with more favourable chemical-physical properties and pharmacological profile in terms of selectivity and tolerability. Because of its molecular complexity, paclitaxel is an ideal candidate for systematic modification to develop an understanding of its structure-activity relationships. Among all the investigated structural changes, two of them - the C-ring opening and the introduction of a functional group in position 14 - led to the compounds studied in this thesis: ION 5390, ION 5614, ION 5738, ION 5839 and ION 6140. The opening of Cring led to C-seco paclitaxel analogues, ION 5390 and ION 5614, while ION 5738, ION 5839 and ION 6140 have an introduction of a functional group in position 14. The main feature of C-seco taxanes is related to their antiangiogenic properties against a scanty cytotoxicity which renders these taxanes cytostatic compounds rather than cytotoxic ones. Whereas the main characteristic of 14-functionalized taxanes is to be poor substrates for P-gp system, showing as a consequence good oral bioavailability, distribution in central nervous system and activity on paclitaxel-resistant tumours. The aim of this project was to characterize the preclinical phannacokinetics of the aforementioned new taxane derivatives. To describe the pharmacokinetic/metabolic profile of these compounds, as first step, it was necessary to develop and validate the assays to determine the concentration of the new derivatives in biological specimens. Consequently, the validated assays were applied to characterize the pharmacokinetics and the bioavailability of the new derivatives in mice after oral and intravenous administration. The methods were based on high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MSIMS) technique, because of its success in phannacokinetic studies with small molecules and due to its high sensitivity and specificity. IDN 5390 and IDN 5614 showed a very high metabolic clearance that limits their systemic disposition and renders advisable a careful characterization of their main metabolites in terms of in vitro biological activity and toxicity, in case of further clinical development. As regards the 14-functionalized derivatives, IDN 5738 and IDN 5839 showed an interesting pharmacokinetic profile, nevertheless superimposable with that of ortataxel - their parent compound under clinical evaluation - against a halved half-life and a comparable cytotoxic activity on two sensitive and resistant human breast tumour cell lines (LCC6/LCC6-MDR and MCF-7IMCF-7-R), rendering them little interesting for further development. The last studied analogue, IDN 6140, seemed to be the most interesting one due to its peculiar pharmacokinetic properties: good bioavailability, very long half-life and high distribution both in normal and tumour brain tissue. It showed considerable reduction in tumour volume in CD 1 xenografted nude mice obtained inoculating orthotopically two human glioma cell lines, U-87 MG and GBM. These results suggest a potential efficacy of this compound for the therapy of central nervous system tumours and brain metastasis.