Increasing drug concentration in a rat lung tumor model by combining isolated lung perfusion with hypertensive chemotherapy.
Isolated left lung perfusion (ILP) with cisplatin was performed in Fisher 344 rats. Before perfusion, bolus injection with endothelin was given via the pulmonary artery. The vasoconstrictive potency was estimated by monitoring the perfusion pressure. The toxicity was estimated by tracking body weight change, survival rate after right pneumonectomy, arterial blood gas analysis and histological findings. To observe the pharmacokinetic changes, a solitary Methylcholanthrene-induced sarcoma model was established in a rat lung and the total platinum concentration in perfused lung and tumor tissues was measured. Perfusion pressure was increased significantly in a dose-dependent manner. Pulmonary toxicity from ILP with cisplatin was limited by the use of endothelin. Significantly higher levels of total platinum were obtained in tumors but not in normal lung tissues by endothelin injection before ILP than by ILP alone. The combination of ILP and hypertensive chemotherapy should be one of the available treatments for unresectable pulmonary carcinoma.