The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

C. Martin, J. Walker, A. Rothnie, R. Callaghan

Research output: Contribution to journalArticle

Abstract

Solid tumours display a complex drug resistance phenotype that involves inherent and acquired mechanisms. Multicellular resistance is an inherent feature of solid tumours and is known to present significant barriers to drug permeation in tumours. Given this barrier, do acquired resistance mechanisms such as P-glycoprotein (P-gp) contribute significantly to resistance? To address this question, the multicellular tumour spheroid (MCTS) model was used to examine the influence of P-gp on drug distribution in solid tissue. Tumour spheroids (TS) were generated from either drug-sensitive MCF7WT cells or a drug-resistant, P-gp-expressing derivative MCF7Adr. Confocal microscopy was used to measure time courses and distribution patterns of three fluorescent compounds; calcein-AM, rhodamine123 and BODIPY-taxol. These compounds were chosen because they are all substrates for P-gp-mediated transport, exhibit high fluorescence and are chemically dissimilar. For example, BODIPY-taxol and rhodamine 123 showed high accumulation and distributed extensively throughout the TSWT, whereas calcein-AM accumulation was restricted to the outermost layers. The presence of P-gp in TSAdr resulted in negligible accumulation, regardless of the compound. Moreover, the inhibition of P-gp by nicardipine restored intracellular accumulation and distribution patterns to levels observed in TSWT. The results demonstrate the effectiveness of P-gp in modulating drug distribution in solid tumour models. However, the penetration of agents throughout the tissue is strongly determined by the physico-chemical properties of the individual compounds.

Original languageEnglish
Pages (from-to)1581-1589
Number of pages9
JournalBritish Journal of Cancer
Volume89
Issue number8
DOIs
Publication statusPublished - Oct 2003

Fingerprint

P-Glycoprotein
Neoplasms
Pharmaceutical Preparations
Paclitaxel
Cellular Spheroids
Rhodamine 123
Nicardipine
Drug Resistance
Confocal Microscopy
Fluorescence
Phenotype

Bibliographical note

Creative Commons Non-commercial Share-alike

Keywords

  • antineoplastic agents
  • multiple drug resistance
  • fluoresceins
  • fluorescent dyes
  • humans
  • confocal microscopy
  • P-glycoprotein
  • paclitaxel
  • rhodamine 123
  • cellular spheroids
  • tumor models

Cite this

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abstract = "Solid tumours display a complex drug resistance phenotype that involves inherent and acquired mechanisms. Multicellular resistance is an inherent feature of solid tumours and is known to present significant barriers to drug permeation in tumours. Given this barrier, do acquired resistance mechanisms such as P-glycoprotein (P-gp) contribute significantly to resistance? To address this question, the multicellular tumour spheroid (MCTS) model was used to examine the influence of P-gp on drug distribution in solid tissue. Tumour spheroids (TS) were generated from either drug-sensitive MCF7WT cells or a drug-resistant, P-gp-expressing derivative MCF7Adr. Confocal microscopy was used to measure time courses and distribution patterns of three fluorescent compounds; calcein-AM, rhodamine123 and BODIPY-taxol. These compounds were chosen because they are all substrates for P-gp-mediated transport, exhibit high fluorescence and are chemically dissimilar. For example, BODIPY-taxol and rhodamine 123 showed high accumulation and distributed extensively throughout the TSWT, whereas calcein-AM accumulation was restricted to the outermost layers. The presence of P-gp in TSAdr resulted in negligible accumulation, regardless of the compound. Moreover, the inhibition of P-gp by nicardipine restored intracellular accumulation and distribution patterns to levels observed in TSWT. The results demonstrate the effectiveness of P-gp in modulating drug distribution in solid tumour models. However, the penetration of agents throughout the tissue is strongly determined by the physico-chemical properties of the individual compounds.",
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The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models. / Martin, C.; Walker, J.; Rothnie, A.; Callaghan, R.

In: British Journal of Cancer, Vol. 89, No. 8, 10.2003, p. 1581-1589.

Research output: Contribution to journalArticle

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T1 - The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models

AU - Martin, C.

AU - Walker, J.

AU - Rothnie, A.

AU - Callaghan, R.

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KW - fluoresceins

KW - fluorescent dyes

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KW - confocal microscopy

KW - P-glycoprotein

KW - paclitaxel

KW - rhodamine 123

KW - cellular spheroids

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