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Enhanced Uptake of Doxorubicin into Bronchial Carcinoma: ß-Glucuronidase Mediates Release of Doxorubicin from a Glucuronide Prodrug (HMR 1826) at the Tumor Site¹

Dr. Margarete Fischer-Bosch-Institut für klinische Pharmakologie, Auerbachstrasse 112, D-70376 Stuttgart [T. E. M., B. S., K. T. K., H. K. K.]; Pathologisches Institut am Robert Bosch Krankenhaus, D-70376 Stuttgart [M. M., P. F.]; Hoechst AG Immunregulation, D-35001 Marburg [K. B.]; and Klinik Schillerhöhe der LVA Württemberg, D-70839 Gerlingen [G. F., A. L., H. T., R. D.], Germany

Lack of tumor selectivity is a severe limitation of cancer chemotherapy. Consequently, reducing dose-limiting organ toxicities such as the cardiac toxicity of doxorubicin (Dox) is of major clinical relevance. Approaches that would facilitate a more tumor-selective anticancer therapy by using nontoxic prodrugs that are converted to active anticancer agents at the tumor site have been the subject of intensive research. One potential method to overcome the cardiac toxicity of Dox is to apply a nontoxic, glucuronide prodrug (HMR 1826) from which Dox is released by the action of ß-glucuronidase, an enzyme present at high levels in many tumors. Using a recently developed, isolated, perfused human lung model, we compared the uptake of Dox into normal lung and lung tumors after a 2.5-h lung perfusion with doxorubicin (n = 8) and with the novel doxorubicin glucuronide prodrug (n = 8). Dox showed a poor uptake into lung tumors as compared with normal lung [mean Dox concentration at the end of perfusion, 1.78 ± 3.11 (median, 0.66) µg/g versus 22.03 ± 10.4 (median, 18.5) µg/g; P < 0.001]. However, after perfusion with HMR 1826, the level of Dox in tumor tissue was about 7-fold higher than after perfusion with Dox itself [14.04 ± 12.9 (median, 12.9) µg/g versus 1.78 ± 3.11 (median, 0.66) µg/g, P < 0.05, n = 8]. In vitro experiments showed a significantly higher ß-glucuronidase expression and activity in the tumors. The extent of in vitro cleavage of HMR 1826 by homogenized lung tissue was closely related to the content of ß-glucuronidase (r = 0.9834, P < 0.0001). When D-saccharolactone, a specific inhibitor of ß-glucuronidase, was added to the perfusate containing HMR 1826, no accumulation of Dox in lung tissue was seen. These data indicate that the high Dox levels achieved in the tumors with HMR 1826 resulted from cleavage of the prodrug by ß-glucuronidase at the tumor site. Thus, the problem of poor Dox uptake into lung tumors could be circumvented by applying the doxorubicin glucuronide prodrug. Several lines of evidence based on both ex vivo and in vitro results indicate that the approach described using a glucuronide prodrug may be useful in facilitating more selective delivery of chemotherapy to tumors in humans.

¹ This work was supported by the Robert Bosch Foundation, Stuttgart, Grant W 7/91/TO1 from the Mildred Scheel Foundation, Bonn, Grant Kr 945/4-2 from the Deutsche Forschungsgemeinschaft, Bonn, and the Landesversicherungsanstalt Württemberg.

² Present address: Department of Clinical Pharmacology, University of Helsinki, FIN-00290 Helsinki, Finland.

³ To whom requests for reprints should be addressed. Phone: 49-711-8101 3705; Fax: 49-711-85 92 95.

Received 12/17/96. Accepted 4/18/97.

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