The importance of tumor glucuronidase in the activation of irinotecan in a mouse xenograft model
| Autor: | Peter Tobin, Peter J. Houghton, Pam J. Cheshire, Laurent P. Rivory, Clinton F. Stewart, Suzan K. Hanna, Helen M. Dodds |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Microdialysis
Transplantation Heterologous Mice SCID Irinotecan Mice Neuroblastoma medicine Animals Humans Incubation Biotransformation Chromatography High Pressure Liquid Glucuronidase Pharmacology Chemistry Brain Neoplasms medicine.disease Molecular biology Antineoplastic Agents Phytogenic In vitro Transplantation Kinetics Biochemistry Molecular Medicine Camptothecin Female Glucuronide Carboxylic Ester Hydrolases Algorithms Neoplasm Transplantation medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 303(2) |
| ISSN: | 0022-3565 |
| Popis: | The anticancer drug irinotecan (CPT-11) is activated to the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin), by esterases. SN-38 is in turn conjugated to the inactive SN-38 glucuronide (SN-38G). The reverse reaction is mediated by beta-glucuronidases. Hence, production of SN-38 may occur through either pathway. In this study we conducted in vitro studies to examine these two reactions in neuroblastoma xenograft tumors (NB1691) and compared the rates of SN-38 production with those observed in the liver and plasma of the host SCID (severe-combined immunodeficient) mice. The rate of formation of SN-38 from CPT-11 by esterases slowed considerably during a 60-min incubation, consistent with the known deacylation-limited nature of this reaction. For xenograft tumor tissue, K(m) and V(max) values of 1.6 microM and 4.4 pmol/min/mg of protein, respectively, were observed. By comparison, these parameters were estimated to be 6.9 microM and 9.4 pmol/min/mg for mouse liver and 2.1 microM and 40.0 pmol/min/mg for mouse plasma, respectively. The formation of SN-38 from SN-38G was very pronounced in both liver and xenograft tumor tissue, in which it was nonsaturable (0.125-50 microM) and time-independent (0-60 min). The derived values of V(max)/K(m) were 0.65 microl/min/mg for the tumor and 2.12 microl/min/mg for the liver preparations. Microdialysate experiments revealed the concentrations of SN-38G and CPT-11 in tumor to be comparable. At equal substrate concentrations, production of SN-38 from SN-38G in tumor extracts was comparable with that from CPT-11. Therefore, reactivation of SN-38 in the tumor by beta-glucuronidases may represent an important route of tumor drug activation for CPT-11. |
| Databáze: | OpenAIRE |
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