Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy.
Irinotecan (CPT-11) is a clinically important anticancer prodrug that requires enzymatic hydrolysis by carboxyesterase to generate the active metabolite SN-38. However, SN-38 is further metabolized to inactive SN-38 glucuronide (SN-38G), thus diminishing the levels of active SN-38. Although exogenously administered glucuronide drugs are being investigated for cancer therapy, it is unknown if endogenously generated camptothecin glucuronide metabolites can be used for tumor therapy. Here, we tested the hypothesis that tumor-located hydrolysis of endogenously generated SN-38G can enhance the antitumor efficacy of CPT-11 therapy. EJ human bladder carcinoma cells expressing membrane-tethered beta-glucuronidase (EJ/mbetaG cells) were used to selectively hydrolyze SN-38G to SN-38. Parental EJ and EJ/mbetaG cells displayed similar in vitro and in vivo growth rates and sensitivities to CPT-11 and SN-38. By contrast, EJ/mbetaG cells were more than 30 times more sensitive than EJ cells to SN-38G, showing that SN-38 could be generated from SN-38G in vitro. Systemic administration of CPT-11 resulted in tumor-located hydrolysis of SN-38G and accumulation of SN-38 in EJ/mbetaG subcutaneous tumors. Importantly, systemic administration of CPT-11, which itself is not a substrate for beta-glucuronidase, dramatically delayed the growth of EJ/mbetaG xenografts without increased systemic toxicity. Thus, the anticancer activity of CPT-11 can be significantly enhanced by converting the relatively high levels of endogenously generated SN-38G to SN-38 in tumors. The high concentrations of SN-38G found in the serum of patients treated with CPT-11 suggest that clinical response to CPT-11 may be improved by elevating beta-glucuronidase activity in tumors.
Prijovich
Zeljko M
ZM
Institute of Biomedical Sciences, Academia Sinica, No. 128, Academia Road, Section 2, 11529 Taipei, Taiwan.
Chen
Kai-Chuan
KC
Roffler
Steve R
SR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D043182:Carboxylesterase / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005965:Glucuronates / Q000494:pharmacology*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D043182:Carboxylesterase; D005966:Glucuronidase; D002166:Camptothecin