A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier

N. Harry Hendrikse, Elisabeth G.E. De Vries, Lizette Eriks-Fluks, Winette T.A. Van Der Graaf, Geke A.P. Hospers, Antoon T.M. Willemsen, Willem Vaalburg, Eric J.F. Franssen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P- glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P- gp function was measured in vivo with positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline (GLC4/P-gp). For validation, in vitro and biodistribution studies with [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC4/P-gp. Biodistribution studies showed 159% and 185% higher levels of [11C]daunorubicin and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors. Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.

Original languageEnglish
Pages (from-to)2411-2416
Number of pages6
JournalCancer Research
Volume59
Issue number10
Publication statusPublished - 15 May 1999

Cite this

Hendrikse, N. H., De Vries, E. G. E., Eriks-Fluks, L., Van Der Graaf, W. T. A., Hospers, G. A. P., Willemsen, A. T. M., ... Franssen, E. J. F. (1999). A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier. Cancer Research, 59(10), 2411-2416.
Hendrikse, N. Harry ; De Vries, Elisabeth G.E. ; Eriks-Fluks, Lizette ; Van Der Graaf, Winette T.A. ; Hospers, Geke A.P. ; Willemsen, Antoon T.M. ; Vaalburg, Willem ; Franssen, Eric J.F. / A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier. In: Cancer Research. 1999 ; Vol. 59, No. 10. pp. 2411-2416.
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title = "A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier",
abstract = "Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P- glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P- gp function was measured in vivo with positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline (GLC4/P-gp). For validation, in vitro and biodistribution studies with [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC4/P-gp. Biodistribution studies showed 159{\%} and 185{\%} higher levels of [11C]daunorubicin and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors. Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp tumors (184{\%}) and in brains (1280{\%}). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.",
author = "Hendrikse, {N. Harry} and {De Vries}, {Elisabeth G.E.} and Lizette Eriks-Fluks and {Van Der Graaf}, {Winette T.A.} and Hospers, {Geke A.P.} and Willemsen, {Antoon T.M.} and Willem Vaalburg and Franssen, {Eric J.F.}",
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Hendrikse, NH, De Vries, EGE, Eriks-Fluks, L, Van Der Graaf, WTA, Hospers, GAP, Willemsen, ATM, Vaalburg, W & Franssen, EJF 1999, 'A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier' Cancer Research, vol. 59, no. 10, pp. 2411-2416.

A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier. / Hendrikse, N. Harry; De Vries, Elisabeth G.E.; Eriks-Fluks, Lizette; Van Der Graaf, Winette T.A.; Hospers, Geke A.P.; Willemsen, Antoon T.M.; Vaalburg, Willem; Franssen, Eric J.F.

In: Cancer Research, Vol. 59, No. 10, 15.05.1999, p. 2411-2416.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier

AU - Hendrikse, N. Harry

AU - De Vries, Elisabeth G.E.

AU - Eriks-Fluks, Lizette

AU - Van Der Graaf, Winette T.A.

AU - Hospers, Geke A.P.

AU - Willemsen, Antoon T.M.

AU - Vaalburg, Willem

AU - Franssen, Eric J.F.

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N2 - Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P- glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P- gp function was measured in vivo with positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline (GLC4/P-gp). For validation, in vitro and biodistribution studies with [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC4/P-gp. Biodistribution studies showed 159% and 185% higher levels of [11C]daunorubicin and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors. Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.

AB - Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P- glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P- gp function was measured in vivo with positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline (GLC4/P-gp). For validation, in vitro and biodistribution studies with [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC4/P-gp. Biodistribution studies showed 159% and 185% higher levels of [11C]daunorubicin and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors. Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.

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Hendrikse NH, De Vries EGE, Eriks-Fluks L, Van Der Graaf WTA, Hospers GAP, Willemsen ATM et al. A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier. Cancer Research. 1999 May 15;59(10):2411-2416.