Digitonin enhances the antitumor effect of cisplatin during isolated lung perfusion

Abstract

Background. The antitumor effect of isolated lung perfusion with cisplatin was limited because the intracellular platinum concentration did not increase sufficiently. To solve this problem, digitonin, a detergent, was chosen to increase cell permeability and enhance intracellular uptake and antitumor effect. This study was designed to investigate toxicity, pharmacokinetics, and efficacy of isolated lung perfusion with the combined use of digitonin and cisplatin in Fischer 344 rats. Methods. Systemic and local toxicities of isolated lung perfusion treatment were evaluated on the basis of body weight change, survival rate, and histologic findings. The maximal tolerated dose of digitonin was determined by assessing survival on day 21 after contralateral pneumonectomy, body weight change, and histologic findings. Pharmacokinetics were observed in a solitary lung tumor nodule model by measuring platinum concentration in tumor and normal lung tissue. The antitumor effect was evaluated by the number of tumor nodules in the left lung 21 days after isolated lung perfusion. Isolated lung perfusion was performed 7 days after 1.0 × 10 6 methylcholanthrene sarcoma cells were injected into the external jugular vein. Results. The maximal tolerated dose of digitonin was 20 μmol/L. Platinum concentration of tumor nodules in the digitonin-cisplatin–treated rats was 20% higher than in the cisplatin-only group (5.48 ± 0.64 μg/g tissue versus 4.50 ± 1.09 μg/g tissue; p = 0.067). The number of pulmonary nodules decreased significantly by digitonin use (1.3 ± 1.5 versus 9.7 ± 2; p < 0.0001). Conclusions. Isolated lung perfusion with digitonin and cisplatin in combination was performed safely and enhanced the antitumor effect. These drugs in combination show promise for enhancing the effect of clinical isolated lung perfusion.