Pharmaceutical and Biomedical Aspects of Topoisomerase I Inhibitors
Pre-clinical and clinical phannacokinetics plays an important rote in the development of new anticancer agents and in the refinement of already existing therapies. In clinical studies, phannacokinetic parameters, including area under the plasma concentration-time curve and/or time above a certain threshold concentration, have previously been shown to be related to the phannacodynamic outcomes, such as myelosuppression or anti-tumor response. In order to obtain reliable phannacokinetic parameters, analytical methodologies have to be developed and validated, enabling accurate detennination of concentrations of anticancer dmgs in biological matrices. These methodologies have to be validated in terms of selectivity, precision, accuracy and sensitivity, to obtain meaningful phannacokinetic results. During the last decade several analogues of the topoisomerase I inhibitor camptothecin have entered clinical practice. Topoisomerase I is a nuclear enzyme involved in the replication of DNA, by fonning a cleavable complex, i.e. the covalent interaction between DNA and the enzyme. The cleavable complex results in a single strand break of the DNA, resulting in relaxation, followed by replication and resealing of the break. The camptothecin topoisomerase I inhibitors reversibly stabilize the cleavable complex, resulting in single·strand DNA breaks and thus termination of DNA replication, subsequently followed by cell death. The camptothecin analogues share a pH-dependent reversible conversion between their pharmacologically active lactone form, which is able to diffuse across cell membranes, and their inactive ring·opened carboxylate form. The existence of the two forms of the camptothecin analogues requires quick sample handling at the site of the patient in order to acquire real·time pharmacokinetic data. In chapter 1, an overview of methodologies for the determination of camptothecin analogues is described and their applicability for pharmacokinetic analysis is discussed. In this thesis, methodologies for the quantitative determination of the topoisomerase I inhibitors topotecan, 9-aminocamptothecin and lurtotecan are described. The applicability of these assays is shown in both clinical pharmacokinetic and in vitro studies.
|Publisher||Erasmus University Rotterdam|
|Promotor||Stoter, G. (Gerrit) , Verweij, J. (Jaap)|
|Sponsor||Alltech / Applied Science Group (Breda, The Netherlands), Gilead Sciences Inc. (Boulder, CO, USA), IDEC Pharmaceuticals Corp. (San Diego, CA, USA), Intersience b.v. (Breda, The Netherlands), SmithKline Beecham Pharma b.v. (Rijswijk, The Netherlands)|
|Keywords||I-inhibitors, neoplastic agents, topoisomerase inhibitors, tumor cells|
Loos, W.J.. (2000, November 15). Pharmaceutical and Biomedical Aspects of Topoisomerase I Inhibitors. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/20422