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 gamma-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 microg/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. Copyright 2003 American Cancer Society.
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 acidgamma-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 humanurothelial 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 microg/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. Copyright 2003 American Cancer Society.
Authors: Roman Rouzier; Radhika Rajan; Peter Wagner; Kenneth R Hess; David L Gold; James Stec; Mark Ayers; Jeffrey S Ross; Peter Zhang; Thomas A Buchholz; Henry Kuerer; Marjorie Green; Banu Arun; Gabriel N Hortobagyi; W Fraser Symmans; Lajos Pusztai Journal: Proc Natl Acad Sci U S A Date: 2005-05-24 Impact factor: 11.205