PURPOSE: Previously, we studied the effect of co-administration of paclitaxel with the second generation ABCB1 (p-gp) modulator valspodar on the intracerebral growth of human U118-MG glioblastoma in nude mice. Valspodar significantly increased the brain levels of paclitaxel by inhibition of p-gp expressed at the blood brain barrier. Thus, the tumour burden was reduced by 90%, which was considered as a proof of concept. However, the paclitaxel dose had to be reduced because of toxic side effects resulting from increased drug levels due to p-gp modulation in peripheral tissues. Therefore, in the present study we examined the co-application of paclitaxel with the third generation ABCB1 modulators elacridar and tariquidar, which were supposed to preferentially modulate p-gp in brain capillaries. METHODS: The inhibitory activity of the modulators was measured by a flow cytometric and a chemosensitivity assay in vitro. To determine the distribution of paclitaxel in vivo, nude mice received 50 mg/kg of valspodar, elacridar or tariquidar p.o. (control: vehicle) 4 h before i.v. injection of 8 mg/kg of paclitaxel. Brain, liver, kidney and plasma were collected and analyzed by RP-HPLC. RESULTS: Our in vitro experiments demonstrate that the new modulators are about 80 times more effective in comparison to valspodar. Co-administration of paclitaxel with elacridar and tariquidar led to a long lasting fivefold increase in the concentration of the cytostatic in the brain. Although the increase (2.5- to 7-fold) tended to be lower compared to that induced by co-administered valspodar (six- to eightfold), the brain/plasma ratios achieved with the new modulators were 2-15 times higher. CONCLUSIONS: Elacridar and tariquidar seem to modulate p-glycoprotein preferentially at the blood-brain barrier. Our results suggest that the systemic toxicity of cytostatics combined with elacridar or tariquidar should be lower than in combination with valspodar.
PURPOSE: Previously, we studied the effect of co-administration of paclitaxel with the second generation ABCB1 (p-gp) modulator valspodar on the intracerebral growth of human U118-MG glioblastoma in nude mice. Valspodar significantly increased the brain levels of paclitaxel by inhibition of p-gp expressed at the blood brain barrier. Thus, the tumour burden was reduced by 90%, which was considered as a proof of concept. However, the paclitaxel dose had to be reduced because of toxic side effects resulting from increased drug levels due to p-gp modulation in peripheral tissues. Therefore, in the present study we examined the co-application of paclitaxel with the third generation ABCB1 modulators elacridar and tariquidar, which were supposed to preferentially modulate p-gp in brain capillaries. METHODS: The inhibitory activity of the modulators was measured by a flow cytometric and a chemosensitivity assay in vitro. To determine the distribution of paclitaxel in vivo, nude mice received 50 mg/kg of valspodar, elacridar or tariquidar p.o. (control: vehicle) 4 h before i.v. injection of 8 mg/kg of paclitaxel. Brain, liver, kidney and plasma were collected and analyzed by RP-HPLC. RESULTS: Our in vitro experiments demonstrate that the new modulators are about 80 times more effective in comparison to valspodar. Co-administration of paclitaxel with elacridar and tariquidar led to a long lasting fivefold increase in the concentration of the cytostatic in the brain. Although the increase (2.5- to 7-fold) tended to be lower compared to that induced by co-administered valspodar (six- to eightfold), the brain/plasma ratios achieved with the new modulators were 2-15 times higher. CONCLUSIONS: Elacridar and tariquidar seem to modulate p-glycoprotein preferentially at the blood-brain barrier. Our results suggest that the systemic toxicity of cytostatics combined with elacridar or tariquidar should be lower than in combination with valspodar.
Authors: A Sparreboom; A S Planting; R C Jewell; M E van der Burg; A van der Gaast; P de Bruijn; W J Loos; K Nooter; L H Chandler; E M Paul; P S Wissel; J Verweij Journal: Anticancer Drugs Date: 1999-09 Impact factor: 2.248
Authors: E Marleen Kemper; A Erik van Zandbergen; Cindy Cleypool; Henk A Mos; Willem Boogerd; Jos H Beijnen; Olaf van Tellingen Journal: Clin Cancer Res Date: 2003-07 Impact factor: 12.531
Authors: Philippe Labrie; Shawn P Maddaford; Jacques Lacroix; Concettina Catalano; David K H Lee; Suman Rakhit; René C Gaudreault Journal: Bioorg Med Chem Date: 2007-03-12 Impact factor: 3.641
Authors: Gergely Szakács; Jill K Paterson; Joseph A Ludwig; Catherine Booth-Genthe; Michael M Gottesman Journal: Nat Rev Drug Discov Date: 2006-03 Impact factor: 84.694
Authors: J van Asperen; O van Tellingen; A Sparreboom; A H Schinkel; P Borst; W J Nooijen; J H Beijnen Journal: Br J Cancer Date: 1997 Impact factor: 7.640
Authors: Crystal R Leibrand; Jason J Paris; Austin M Jones; Quamrun N Masuda; Matthew S Halquist; Woong-Ki Kim; Pamela E Knapp; Angela D M Kashuba; Kurt F Hauser; MaryPeace McRae Journal: J Neurovirol Date: 2019-05-17 Impact factor: 2.643
Authors: Florian Bauer; Claudia Kuntner; Jens P Bankstahl; Thomas Wanek; Marion Bankstahl; Johann Stanek; Severin Mairinger; Bernd Dörner; Wolfgang Löscher; Markus Müller; Thomas Erker; Oliver Langer Journal: Bioorg Med Chem Date: 2010-06-22 Impact factor: 3.641