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Epirubicin and meglumine ?-linolenic acid: a logical choice of combination therapy for patients with superficial bladder carcinoma

Epirubicin and meglumine ?-linolenic acid: a logical choice of combination therapy for patients with superficial bladder carcinoma
Epirubicin and meglumine ?-linolenic acid: a logical choice of combination therapy for patients with superficial bladder carcinoma
BACKGROUND Anthracyclines have been established as first-line drugs for intravesical use in the treatment of patients with superficial bladder carcinoma, although they result only in a modest reduction in tumor recurrence rates. The essential fatty acid -linolenic acid (GLA) also is an effective cytotoxic agent against superficial bladder carcinoma when it is applied topically. The objective of this study was to assess the efficacy of combined epirubicin and GLA with the purpose of developing a suitable model for modification of existing intravesical regimens.
METHODS The human urothelial carcinoma cell lines MGH-U1 and RT112 were used in standard cytotoxicity assays and were exposed to meglumine GLA (MeGLA) and epirubicin in two-dimensional concentration matrices. A thiozolyl blue (methyl-thiazoldiphenyl tetrazolium) assay was used to determine residual cell biomass. Drug interaction was quantified by median-effect analysis software (CalcuSyn®), and the evaluation of drug uptake utilized fluorescence confocal microscopy (FCM) and flow cytometry.
RESULTS MeGLA caused a significant enhancement of anthracycline uptake, viewed by FCM, from 92 fluorescence units to 222 fluorescence units (P < 0.001). Flow cytometry confirmed the increased drug uptake and showed that the mean epirubicin content per cell increased from 23 to 57 units and from 8 to 24 units for MGH-U1 and RT112 cells, respectively (99% confidence interval < 0.3). This resulted in improved cytotoxicity, and it was shown that the drugs acted synergistically with all but the highest MeGLA concentrations.
CONCLUSIONS The efficacy of epirubicin was enhanced significantly when it was used in combination with most concentrations of MeGLA (< 300 g/mL), and the two agents acted synergistically. There was a corresponding increase in epirubicin uptake by cells under these conditions. At high MeGLA concentrations, however, anthracycline solubility was compromised, and drug synergy was lost.
anthracyclines, combination therapy, intravesical chemotherapy, meglumine y-linolenic acid, superficial bladder carcinoma
0008-543X
71-78
Harris, Neil M.
24df00e7-9733-4bb2-9bb5-847eba940d67
Anderson, William R.
6f2251c8-0f87-41b6-a568-f568eca53552
Lwaleed, Bashir A.
e7c59131-82ad-4a14-a227-7370e91e3f21
Cooper, Alan J.
65dcd1e1-3fcd-46b8-ad5f-f17e0d5b80a5
Birch, Brian R.
536ee8d2-9cf9-4412-a29b-d2267fa9d765
Solomon, Lemke Z.
504b8fb4-9a53-47ac-9c15-0cbfb8d81f58
Harris, Neil M.
24df00e7-9733-4bb2-9bb5-847eba940d67
Anderson, William R.
6f2251c8-0f87-41b6-a568-f568eca53552
Lwaleed, Bashir A.
e7c59131-82ad-4a14-a227-7370e91e3f21
Cooper, Alan J.
65dcd1e1-3fcd-46b8-ad5f-f17e0d5b80a5
Birch, Brian R.
536ee8d2-9cf9-4412-a29b-d2267fa9d765
Solomon, Lemke Z.
504b8fb4-9a53-47ac-9c15-0cbfb8d81f58

Harris, Neil M., Anderson, William R., Lwaleed, Bashir A., Cooper, Alan J., Birch, Brian R. and Solomon, Lemke Z. (2003) Epirubicin and meglumine ?-linolenic acid: a logical choice of combination therapy for patients with superficial bladder carcinoma. Cancer, 97 (1), 71-78. (doi:10.1002/cncr.11055).

Record type: Article

Abstract

BACKGROUND Anthracyclines have been established as first-line drugs for intravesical use in the treatment of patients with superficial bladder carcinoma, although they result only in a modest reduction in tumor recurrence rates. The essential fatty acid -linolenic acid (GLA) also is an effective cytotoxic agent against superficial bladder carcinoma when it is applied topically. The objective of this study was to assess the efficacy of combined epirubicin and GLA with the purpose of developing a suitable model for modification of existing intravesical regimens.
METHODS The human urothelial carcinoma cell lines MGH-U1 and RT112 were used in standard cytotoxicity assays and were exposed to meglumine GLA (MeGLA) and epirubicin in two-dimensional concentration matrices. A thiozolyl blue (methyl-thiazoldiphenyl tetrazolium) assay was used to determine residual cell biomass. Drug interaction was quantified by median-effect analysis software (CalcuSyn®), and the evaluation of drug uptake utilized fluorescence confocal microscopy (FCM) and flow cytometry.
RESULTS MeGLA caused a significant enhancement of anthracycline uptake, viewed by FCM, from 92 fluorescence units to 222 fluorescence units (P < 0.001). Flow cytometry confirmed the increased drug uptake and showed that the mean epirubicin content per cell increased from 23 to 57 units and from 8 to 24 units for MGH-U1 and RT112 cells, respectively (99% confidence interval < 0.3). This resulted in improved cytotoxicity, and it was shown that the drugs acted synergistically with all but the highest MeGLA concentrations.
CONCLUSIONS The efficacy of epirubicin was enhanced significantly when it was used in combination with most concentrations of MeGLA (< 300 g/mL), and the two agents acted synergistically. There was a corresponding increase in epirubicin uptake by cells under these conditions. At high MeGLA concentrations, however, anthracycline solubility was compromised, and drug synergy was lost.

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More information

Published date: 1 January 2003
Keywords: anthracyclines, combination therapy, intravesical chemotherapy, meglumine y-linolenic acid, superficial bladder carcinoma

Identifiers

Local EPrints ID: 19317
URI: http://eprints.soton.ac.uk/id/eprint/19317
ISSN: 0008-543X
PURE UUID: ff7ca417-17d4-490d-814e-bb3f3792c394

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Date deposited: 01 Feb 2006
Last modified: 15 Mar 2024 06:14

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Contributors

Author: Neil M. Harris
Author: William R. Anderson
Author: Alan J. Cooper
Author: Brian R. Birch
Author: Lemke Z. Solomon

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