Dose Optimization of a Doxorubicin Prodrug (HMR 1826) in Isolated Perfused Human Lungs: Low Tumor pH Promotes Prodrug Activation by β-Glucuronidase

Mürdter, Thomas E.; Friedel, Godehard; Backman, Janne T.; McClellan, Monika; Schick, Monika; Gerken, Manfred; Bosslet, Klaus; Fritz, Péter; Toomes, H.; Kroemer, Heyo K.; Sperker, Bernhard

doi:10.1124/jpet.301.1.223

Cited by 49 publications

(47 citation statements)

References 20 publications

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“…The sensitivity of EJ and EJ/mβG cells to CPT-11, SN-38, and SN-38G was investigated at neutral pH (pH 7.4) or at the slightly acidic pH (pH 6.6) found in some tumors (29). Both the cell lines were equally sensitive to CPT-11 or SN-38 in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy

Prijovich

Chen

Roffler

2009

Molecular Cancer Therapeutics

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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 β-glucuronidase (EJ/mβG cells) were used to selectively hydrolyze SN-38G to SN-38. Parental EJ and EJ/mβG cells displayed similar in vitro and in vivo growth rates and sensitivities to CPT-11 and SN-38. By contrast, EJ/mβG 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/ mβG subcutaneous tumors. Importantly, systemic administration of CPT-11, which itself is not a substrate for β-glucuronidase, dramatically delayed the growth of EJ/ mβG 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 β-glucuronidase activity in tumors. [Mol Cancer Ther 2009;8(4):940-6]

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Section: Discussionmentioning

confidence: 99%

“…Thus, cellular sensitivity to glucuronide drugs correlates with extracellular rather than intracellular βG activity (21). Membrane-tethered βG is accessible to hydrolyze SN-38G to SN-38, resulting in dramatically enhanced (29,30). Treatment of mice bearing established tumors with i.v.…”

Section: Discussionmentioning

confidence: 99%

Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy

Prijovich

Chen

Roffler

2009

Molecular Cancer Therapeutics

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“…bG is considered as a tumor marker (14,15,20) and a prodrug-activating enzyme for cancer prodrug therapies (35,36). Connors and Whisson demonstrated that high bG levels present in plasmacytomas were correlated with higher drug sensitivity of the tumors (37).…”

Section: Discussionmentioning

confidence: 99%

“…injected with 131 I-TrapG and then examined by measuring radioactivity of the probe in organs at 1,8,20, and 40 hours after probe injection. Consistent with the micro-PET analysis, mean radioactivity of CT26/mbG tumors was significantly higher than the CT26 tumors (Fig.…”

Section: Biodistribution Of the 131 I-trapg In Micementioning

confidence: 99%

“…Elevated levels of bG present in the tumor environment are believed to be due to tumor overexpression (14) and release from necrotic tumor tissues (19) or tumor-infiltrating immune cells (15). Because bG has been considered as a tumor marker (14,15,20), it would be very useful to image bG activity in vivo to personalize glucuronide prodrug treatment and greatly improve exogenous or endogenous bG-based targeted therapy.…”

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confidence: 99%

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PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

Cheng

Leu

et al. 2014

Molecular Cancer Therapeutics

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Beta-glucuronidase (bG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image bG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of bG activity for medical usage is not yet available. Here, we developed a radioactive bG activity-based trapping probe for positron emission tomography (PET). We generated a 124 I-tyramine-conjugated difluoromethylphenol beta-glucuronide probe (TrapG) to form 124 I-TrapG that could be selectively activated by bG for subsequent attachment of 124 I-tyramine to nucleophilic moieties near bG-expressing sites. We estimated the specificity of a fluorescent FITC-TrapG, the cytotoxicity of tyramine-TrapG, and the serum half-life of 124 I-TrapG. bG targeting of 124 I-TrapG in vivo was examined by micro-PET. The biodistribution of 131 I-TrapG was investigated in different organs. Finally, we imaged the endogenous bG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at bG-expressing CT26 (CT26/mbG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. 124 ITrapG preferentially accumulated in CT26/mbG but not CT26 cells. Meanwhile, micro-PET and wholebody autoradiography results demonstrated that 124 I-TrapG signals in CT26/mbG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous bG can be monitored by using infrared glucuronide trapping probes (NIR-TrapG) and suppressed by 9ACG prodrug treatment. 124 I-TrapG exhibited low cytotoxicity allowing long-term monitoring of bG activity in vivo to aid in the optimization of prodrug targeted therapy.

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Precision‐Cut Lung Slices (PCLS)

Martin

Uhlig

2012

Replacing Animal Models

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Dose Optimization of a Doxorubicin Prodrug (HMR 1826) in Isolated Perfused Human Lungs: Low Tumor pH Promotes Prodrug Activation by β-Glucuronidase

Cited by 49 publications

References 20 publications

Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy

Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy

PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

Precision‐Cut Lung Slices (PCLS)

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