Epirubicin and meglumine gamma-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 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.
Harris
Neil M
NM
Solent Department of Urology, St. Mary's Hospital, Portsmouth, Hampshire, United Kingdom. neilandjane@supanet.com
Anderson
William R
WR
Lwaleed
Bashir A
BA
Cooper
Alan J
AJ
Birch
Brian R
BR
Solomon
Lemke Z
LZ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005434:Flow Cytometry; D006801:Humans; D008536:Meglumine / Q000737:chemistry; D018613:Microscopy, Confocal; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017965:gamma-Linolenic Acid / Q000008:administration & dosage
D015251:Epirubicin; D008536:Meglumine; D017965:gamma-Linolenic Acid