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.