P-glycoprotein modulation by valspodar and cyclosporin does not increase tumor uptake of doxorubicin administered via isolated lung perfusion to rats bearing sarcoma lung metastases.
BACKGROUND: Isolated lung perfusion (ILP) with doxorubicin allows a regional increase in drug exposure while sparing unaffected tissues, but clinical results have so far been disappointing, presumably in part because of the limited tumor penetration of doxorubicin. The aim of this study was to assess whether tumor uptake of doxorubicin, administered locoregionally by ILP, would be increased by the administration of P-glycoprotein (P-gp) modulators. MATERIALS AND METHODS: Single-pass antegrade ILP (A-ILP) was performed with doxorubicin in rats bearing a pulmonary sarcoma nodule which were either untreated or received P-gp inhibitors cyclosporin, valspodar or the vehicle, Cremophor(R), only. Doxorubicin concentrations in tumor, lung and effluent were measured by high performance liquid chromatography (HPLC) coupled to spectrofluorimetric detection and the expression of P-gp was examined by Western blot in tumors and lungs. RESULTS: Doxorubicin concentrations in tumors were 5- to 10-fold lower than those measured in lungs tissues. Doxorubicin penetration in tumors, expressed as tumor retention ratios (TR60min), were not different between the groups. Western blot analysis did not show any evidence of baseline or doxorubicin-induced P-gp expression in the tumor model. CONCLUSION: P-gp modulation with cyclosporin or valspodar fails to increase the tumor uptake of doxorubin administered by A-ILP. Other reasons for low doxorubicin penetration in tumor, such as high interstitial fluid pressure or tumor vasculature barrier, or alternate cell membrane drug transporters, need to be examined for a better understanding of impaired doxorubicin delivery to tumor.