ENHANCED UPTAKE OF DOXORUBICIN INTO BRONCHIAL-CARCINOMA - BETA-GLUCURONIDASE MEDIATES RELEASE OF DOXORUBICIN FROM A GLUCURONIDE PRODRUG (HMR-1826) AT THE TUMOR SITE

Lack of tumor selectivity is a severe limitation of cancer chemotherap y. Consequently, reducing dose-limiting organ toxicities such as tile cardiac toxicity of doxorubicin (Dox) is of major clinical relevance. Approaches that would facilitate a more tumor-selective anticancer the rapy by using nontoxic prodrugs that are converted to active anticance r agents at the tumor site have been the subject of intensive research . One potential method to overcome the cardiac toxicity of Dox is to a pply a nontoxic, glucuronide prodrug (HMR 1826) from which Dox is rele ased by the action of beta-glucuronidase, an enzyme present at high le vels in many tumors. Using a recently developed, isolated, perfused hu man lung model, we compared the uptake of Dox into normal lung and lun g tumors after a 2.5-h lung perfusion with doxorubicin (n = 8) and wit h the novel doxorubicin glucuronide prodrug (n = 8). Dox showed a poor uptake into lung tumors as compared with normal lung [mean Dox concen tration at the end of perfusion, 1.78 +/- 3.11 (median, 0.66) mu g/g v ersus 22.03 +/- 10.4 (median, 18.5) mu g/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 (med ian, 12.9) mu g/g versus 1.78 +/- 3.11 (median, 0.66) mu g/g, P < 0.05 , n = 8]. In vitro experiments showed a significantly higher beta-gluc uronidase expression and activity in the tumors. The extent of in vitr o cleavage of HMR 1826 by homogenized lung tissue was closely related to the content of beta-glucuronidase (r = 0.9834, P < 0.0001). When D- saccharolactone, a specific inhibitor of beta-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 beta-glucuronidase at the tumor site. Thus, the problem of poor Dox up take into lung tumors could be circumvented by applying the doxorubici n glucuronide prodrug. Several lines of evidence based on both ex vivo and lit vitro results indicate that the approach described using a gl ucuronide prodrug may be useful in facilitating more selective deliver y of chemotherapy to tumors in humans.