β-葡萄糖酸苷酶(β-glucuronidase)以經被廣泛使用於活化前驅藥物之標靶治 療。目前已經有許多葡萄糖酸苷前驅藥物被證實可用於腫瘤治療。若能夠於治療 前評估前驅藥物之治療效果，將對β-葡萄糖酸苷酶為主的個人化前驅藥物之標 靶治療相當的重要。然而目前臨床沒有相關文獻指出，腫瘤的β-葡萄糖酸苷酶 高低與前驅藥物的治療效果具有關連性。而我們先前的成果顯示，遠紅光之葡萄 醣醛酸造影劑(NIR-TrapG)可以經由β-葡萄醣酸苷酶催化產生共價鍵結，相較於 CT26(對照組)可累積在表現βG 的CT26/mβG 腫瘤。甚至可以追蹤深層肝臟移植 的CT26/mβG 腫瘤。此外我們在透過腺病毒攜帶βG 基因進行基因治療的結果中 顯示，增加腫瘤區域之βG 活性可以增加CPT-11 與葡萄醣酸苷前驅藥物(SN38-G, 9ACG)之療效。基於上述的成果，我們預計以造影腫瘤內生性的βG 評估β-葡萄 糖酸苷酶為主的個人化前驅藥物之標靶治療。為達到這個目的，我們將進行(1) 檢測人類腫瘤細胞內生性βG 活性與對藥物敏感性之相關性，(2)於活體檢測人類 腫瘤內生性βG 活性與藥物治療效果之相關性。我們將以NIR-TrapG 非侵犯性造 影檢測不同腫瘤內生性βG 活性，以進行個人化前驅藥物之腫瘤標靶治療。我們 相信本計畫若成功，將能提供治療前/後評估酵素活性藥物療效的平台，成為個 人化葡萄醣酸苷前驅藥物之標靶治療及療效評估之指標。 β-glucuronidase (βG) is an attractive prodrug-converting enzyme for selective chemotherapy therapy. Several glucuronide prodrugs have been synthesized for βG and shown to produce potent anti-tumor activity. The ability to access the therapeutic efficacy of glucuronide prodrugs would be ideal to personalize βG based enzyme prodrug therapy. However, clinical studies have not yet clarified the relationship between antitumor effect and βG activity in tumors. Our previous results demonstrate that the near infrared glucuronide probe (NIR-TrapG) can be activated by βG and accumulate in βG-expreccing tumors (CT26/mβG) rather than control tumor. The NIR-TrapG also allows monitoring of the βG-expression in CT26/mβG tumors transplanted deep in the liver. In addition, we also demonstrated that using adenovirus to increase expression of βG can enhance the antitumor activity of CPT-11 and glucuronide prorugs (SN38G, 9ACG). Based on those results, we propose to image the endogenous βG activity for personalized glucuronide prodrug target therapy. Toward this goal, we have two specific aims: (1) investigate the correlation between cellular endogenous βG activity and drug sensitivity, (2) investigate the in vivo correlation between tumor endogenous βG and therapeutic efficiency of anti-tumor drugs. We will use NIR-trapG for screening tumors with βG over-expression and to monitor the efficacy of glucuronide prodrugs in personalized anti-cancer therapy. We believe that, upon completion, monitoring endogenous enzyme activity for accessing the therapeutic efficacy of prodrugs will provide a valuable tool for personalized enzyme based prodrug target therapy.
