Variability of cyclophosphamide uptake into human bronchial carcinoma: consequences for local bioactivation

Purpose: The alkylating cytostatic prodrug cyclophosphamide is bioactivated by the human cytochrome P450 enzyme system. Since these enzymes are not on ly expressed in human liver, but also in extrahepatic tissue, local bioacti vation of this drug may play an important role in its antineoplastic effect s, e.g., chemotherapy of lung tumors. This would require uptake of signific ant amounts of cyclophosphamide into tumor tissue, which has not yet been d emonstrated. Methods: We used a recently developed, ex vivo isolated, venti lated and perfused human lung model to study cyclophosphamide uptake into b ronchial carcinoma and healthy lung tissue. Following a standard lobectomy, lung samples containing the tumor were perfused with buffer containing 2 m M cyclophosphamide for 2 h. Cyclophosphamide concentrations in perfusate an d healthy peripheral tissue were measured during the perfusion and in tumor s at the end of perfusion. Results: In all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a tissue to perfusate ratio of 0. 021. Moreover, in tumor samples, cyclophosphamide concentrations were signi ficantly lower(P < 0.05) than in healthy lung tissue and showed pronounced interindividual variability. Median concentrations were 36.8 mu g/g(26.9-44 .2 mu g/g) in healthy tissue and 5.1 mu g/g (0.0-26.8 mu g/g) in tumor samp les. Tumor cyclophosphamide concentrations varied between 0 and 75% of thos e reached in healthy tissue. Conclusions: Our results indicate that CP tumo r concentrations are modulated by factors different from dose and that expr ession of bioactivating enzymes in human lung or transfection of genes enco ding these enzymes into tumor cells does not necessarily lead to local bioa ctivation of cyclophosphamide.