The influence of expression of P-glycoprotein on the penetration of anticancer drugs through multicellular layers

Tunggal, Jonathan K.; Melo, Tricia; Ballinger, James R.; Tannock, Ian F.

doi:10.1002/(sici)1097-0215(20000401)86:1<101::aid-ijc16>3.0.co;2-i

Cited by 41 publications

(34 citation statements)

References 16 publications

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“…The results presented for calcein-AM and those for doxorubicin (Wartenberg and Acker, 1996;Tunggal et al, 2000) show that P-gp is able to prevent the accumulation of compounds with a relatively 'restricted' distribution pattern. Does it afford a similar effect on the penetration of compounds with different physico-chemcal properties?…”

Section: Discussionmentioning

confidence: 95%

“…This effect would result from a lack of significant reduction in extracellular concentration during passage due to the reduced accumulation in cells. This hypothesis was supported by the reduced penetration of [ 14 C]doxorubicin through TS following inhibition of P-gp, thereby producing toxicity in perivascular cells while preventing access to central quiescent cells (Tunggal et al, 2000). However, doxorubicin distribution may not provide a 'global' or typical template for drug distribution due to the sequestration within the outer cell population caused by its avid binding to cellular macromolecules (Sutherland et al, 1979;Kwok and Twentyman, 1985;Tunggal et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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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 MCF7 WT cells or a drug-resistant, P-gp-expressing derivative MCF7 Adr . 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 TS WT , whereas calcein-AM accumulation was restricted to the outermost layers. The presence of P-gp in TS Adr 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 TS WT . 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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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…Our third hypothesis, that the modifiers might improve the poor penetration of doxorubicin and mitoxantrone through tumour tissue was based on previous studies indicating that drug penetration was largely through the extracellular space and that mechanisms that decreased cellular uptake of drugs improved their tissue penetration (Tunggal et al, 2000;Cowan and Tannock, 2001). Decreased uptake of basic drugs into endosomes might be expected to lead to a decrease in the their total cellular accumulation, although endosomes are also known to fuse with the cell membrane and deposit their contents extracellularly (Schindler et al, 1996;Simon, 1999), so this will depend on the rate of endosomal recycling.…”

Section: Discussionmentioning

confidence: 99%

“…While these mechanisms are important, solid tumours have a poorly formed vasculature and an additional explanation for the lack of effectiveness of many anticancer drugs may be their limited ability to penetrate through multiple cell layers of the extravascular space to reach all of the tumour cells (Durand, 1989;Jain, 1990;Hicks et al, 1997;Phillips et al, 1998;Lankelma et al, 1999;Tunggal et al, 1999;Tannock et al, 2002). The multicellular layer (MCL) model allows tumour cells to be grown in culture with many properties of tumours in vivo, including desmosomes between cells and an extracellular matrix (Hicks et al, 1997;Minchinton et al, 1997;Phillips et al, 1998;Tunggal et al, 1999Tunggal et al, , 2000Cowan and Tannock, 2001;Tannock et al, 2002). Multicellular layers provide a simple, direct and quantitative means for measuring the penetration of drugs through solid tissue.…”

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confidence: 99%

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Inhibition of endosomal sequestration of basic anticancer drugs: influence on cytotoxicity and tissue penetration

Lee

Tannock

2006

Br J Cancer

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The basic drugs doxorubicin and mitoxantrone are known to be concentrated in acidic endosomes of cells. Here, we address the hypotheses that raising endosomal pH with the modifying agents chloroquine, omeprazole or bafilomycin A might decrease sequestration of anticancer drugs in endosomes, thereby increasing their cytotoxicity and availability for tissue penetration. Chloroquine, omeprazole and bafilomycin A showed concentration-dependent effects to raise endosomal pH, and to inhibit sequestration of doxorubicin in endosomes. Chloroquine and omeprazole but not bafilomycin A decreased the net uptake of doxorubicin into cells, but there was no significant effect on uptake of mitoxantrone. Omeprazole and bafilomycin A increased the cytotoxicity of the anticancer drugs for cultured cells, as measured in a clonogenic assay, whereas chloroquine had minimal effects on cytotoxicity despite reduced uptake of doxorubicin. Omeprazole but not chloroquine or bafilomycin A increased the penetration of anticancer drugs through multicellular layers of tumour tissue. We conclude that modifiers of endosomal pH might increase therapeutic effectiveness of basic drugs by increasing their toxicity and/or tissue penetration in solid tumours.

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Drug Penetration and Therapeutic Resistance

Minchinton

Kyle

2010

Tumor Microenvironment

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The influence of expression of P-glycoprotein on the penetration of anticancer drugs through multicellular layers

Cited by 41 publications

References 16 publications

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

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

Inhibition of endosomal sequestration of basic anticancer drugs: influence on cytotoxicity and tissue penetration

Drug Penetration and Therapeutic Resistance

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