Regional chemotherapy for bladder neoplasms using continuous intravesical infusion of doxorubicin: impact of concomitant administration of dimethyl sulfoxide on drug absorption and antitumor activity.

Abstract

One objective of regional chemotherapy is to achieve the therapeutic drug levels in local tissues and primary nodal drainage fields, while minimizing systemic drug toxicity. The composition of the drug-delivery vehicle may influence local drug absorption and thereby modulate both tissue drug levels and systemic toxicity. We evaluated the effect of dimethyl sulfoxide (DMSO) as a drug-delivery vehicle on regional and systemic levels of doxorubicin (DOX) and on the cytotoxicity of DOX following continuous intravesical administration in an invasive rat transitional cell bladder carcinoma model. F344 rats received continuous intravesical DOX infusion for a 7-day period using a regional drug administration system. A constant dose of DOX was administered in one of three DMSO concentrations (0%, 10%, or 50%) to groups of animals (N = 20 per group). These concentrations corresponded to target urinary concentrations of 0%, 0.1%, and 0.5%, respectively. DOX levels in urine, serum, muscle, liver, bladder wall, and retroperitoneal lymph nodes were measured using a fluorescence assay on experimental days 0, 2, 4, 6, and 8 (N = four animals/group per day). In vitro assays evaluated the effect of DMSO concentration on the cytotoxicity of DOX against six transitional cell carcinoma cell lines. A final experiment on rats with established bladder tumors compared the cytoreductive effect of continuous intravesical infusion of DOX in 50% DMSO with that of DOX alone and with that in a sham-treated control group; there were 20 rats in each group. Mean and peak tissue and serum levels of DOX increased as a direct function of DMSO concentration. Compared with the results in controls, mean concentrations of DOX in the bladder were increased 7.1-fold and 12.1-fold in the groups given 10% and 50% DMSO, respectively. Average drug concentrations in the lymph nodes were increased 9.6-fold and 9.3-fold in the groups given 10% and 50% DMSO, respectively. In vitro, DMSO synergistically enhanced the cytotoxicity of DOX in two of the six cell lines studied. Solubilizing the test agent in 5% DMSO reduced the IC50 (drug concentration required to reduce cell viability to 50% of control values) to an average of 56% +/- 41% (+/- SD) of control values; 10% DMSO further decreased the average IC50 to 20% +/- 18% (+/- SD) of control values. The mean bladder tumor weight of animals treated with the combination of DOX and DMSO was 0.52 g. This compared with a mean tumor-bearing bladder weight of 2.69 g in the control group (P = .012) and 0.80 g in the group treated with DOX alone (P = .0544). These results suggest that the use of DMSO as a solvent vehicle for DOX improves drug absorption while simultaneously potentiating DOX cytotoxicity. The use of DMSO as a drug carrier merits further evaluation as a way of enhancing the efficacy of regional chemotherapy regimens.