Phase II study of irinotecan and amrubicin in patients with relapsed non-small cell lung cancer: Okayama Lung Cancer Study Group Trial 0402

Nogami, Naoyuki; Hotta, Katsuyuki; Segawa, Yoshihiko; Takigawa, Nagio; Hosokawa, Shinobu; Oze, Isao; Fujii, Masanori; Ichihara, Eiki; Shibayama, Takuo; Tada, Atsuhiko; Hamada, Noboru; Uno, Masatoshi; Tamaoki, Akihiko; Kuyama, Shoichi; Ikeda, Genyo; Osawa, Masahiro; Takata, Saburo; Tabata, Masahiro; Tanimoto, Mitsune; Kiura, Katsuyuki

doi:10.3109/0284186x.2011.648342

Cited by 9 publications

(5 citation statements)

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“…34,52,53 Irinotecan is currently in clinical trials for neuroblastoma, 54 colon cancer, 55 and other solid malignancies. 56−60 New strategies to more effectively activate irinotecan by modified rabbit and human carboxylesterases are in development. 34,52 We reasoned that our new split esterase system could potentially be used to activate irinotecan analogues in an orthogonal and programmable manner.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, we tested the utility of the split esterase to unmask a pharmacological agent in a proximity-dependent manner. The prodrug irinotecan (CPT-11) is converted to the cytotoxic active metabolite SN-38, a 1000-fold more potent topoisomerase-1 inhibitor, by carboxylesterases. ,, Irinotecan is currently in clinical trials for neuroblastoma, colon cancer, and other solid malignancies. − New strategies to more effectively activate irinotecan by modified rabbit and human carboxylesterases are in development. , We reasoned that our new split esterase system could potentially be used to activate irinotecan analogues in an orthogonal and programmable manner. We therefore synthesized a new methyl-cyclopropyl-masked version of irinotecan to generate SN-38-CM 2 (Figure a, Note S3).…”

Section: Resultsmentioning

confidence: 99%

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Development of a Split Esterase for Protein–Protein Interaction-Dependent Small-Molecule Activation

Kentala

Beck

et al. 2019

ACS Cent. Sci.

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Split reporters based on fluorescent proteins and luciferases have emerged as valuable tools for measuring interactions in biological systems. Relatedly, biosensors that transduce measured input signals into outputs that influence the host system are key components of engineered gene circuits for synthetic biology applications. While small-molecule-based imaging agents are widely used in biological studies, and small-molecule-based drugs and chemical probes can target a range of biological processes, a general method for generating a target small molecule in a biological system based on a measured input signal is lacking. Here, we develop a proximity-dependent split esterase that selectively unmasks ester-protected small molecules in an interaction-dependent manner. Exploiting the versatility of an ester-protected small-molecule output, we demonstrate fluorescent, chemiluminescent, and pharmacological probe generation, each created by masking key alcohol functional groups on a target small molecule. We show that the split esterase system can be used in combination with ester-masked fluorescent or luminescent probes to measure protein–protein interactions and protein–protein interaction inhibitor engagement. We demonstrate that the esterase-based reporter system is compatible with other commonly used split reporter imaging systems for the simultaneous detection of multiple protein–protein interactions. Finally, we develop a system for selective small-molecule-dependent cell killing by unmasking a cytotoxic molecule using an inducible split esterase. Presaging utility in future synthetic biology-based therapeutic applications, we also show that the system can be used for intercellular cell killing via a bystander effect, where one activated cell unmasks a cytotoxic molecule and kills cells physically adjacent to the activated cells. Collectively, this work illustrates that the split esterase system is a valuable new addition to the split protein toolbox, with particularly exciting potential in synthetic biology applications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Development of a Split Esterase for Protein–Protein Interaction-Dependent Small-Molecule Activation

Kentala

Beck

et al. 2019

ACS Cent. Sci.

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“…Diagnosed with the lung cancer (T4N3M1, stage IV), she received a combination of cisplatin (80 mg/m 2 , day 1) and docetaxel (60 mg/m 2 , day 1), followed by gefitinib (250 mg/body), pemetrexed (500 mg/m 2 , day 1), erlotinib (150 mg/body), or a combination of irinotecan (80 mg/m 2 , days 1 and 8) and amrubicin (80 mg/m 2 , days 1 and 8). Although the combination of irinotecan and amrubicin was our original regimen [5], others were standard first line chemotherapy or salvage treatments. With these treatments, she did not achieve a partial response, although the lymph node specimen carried an EGFR deletion mutation, L747-T751 in exon 19.…”

Section: Case Presentationmentioning

confidence: 99%

Disappearance of an activated EGFR mutation after treatment with EGFR tyrosine kinase inhibitors

et al. 2012

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“…The prodrug irinotecan (CPT-11) is converted to the cytotoxic active metabolite SN-38, a 1,000-fold more potent topoisomerase-1 inhibitor, by carboxylesterases 31,48,49 . Irinotecan is currently in clinical trials for neuroblastoma 50 , colon cancer 51 , and other solid malignancies [52][53][54][55][56] . New strategies to more effectively activate irinotecan by modified rabbit and human carboxylesterases are also in development.…”

Section: Proximity-dependent Uncaging Of Bioactive Moleculesmentioning

confidence: 99%

Development of a Split Esterase for Protein-Protein Interaction Dependent Small Molecule Activation

Kentala¹,

Beck²,

An³

et al. 2019

Preprint

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Split reporters based on fluorescent proteins and luciferases have emerged as valuable tools for measuring interactions in biological systems. Relatedly, biosensors that transduce measured input signals into outputs that influence the host system are key components of engineered gene circuits for synthetic biology applications. While small molecule-based imaging agents are widely used in biological studies, and small molecule-based drugs and chemical probes can target a range of biological processes, a general method for generating a target small molecule in a biological system based on a measured input signal is lacking. Here, we develop a proximity-dependent split esterase that selectively unmasks ester-protected small molecules in an interaction-dependent manner. Exploiting the versatility of an ester-protected small molecule output, we demonstrate fluorescent, chemiluminescent, and pharmacological probe generation, each created by masking key alcohol functional groups on a target small molecule. We show the split esterase system can be used in combination with ester-masked fluorescent or luminescent probes to measure a protein-protein interactions and protein-protein interaction inhibitor engagement. We demonstrate the esterase-based reporter system is compatible with other commonly-used split reporter imaging systems for the simultaneous detection of multiple protein-protein interactions. Finally, we develop a system for selective small molecule-dependent cell killing by unmasking a cytotoxic molecule using an inducible split esterase. Presaging utility in future synthetic biology-based therapeutic applications, we also show the system can be used for intercellular cell killing via a bystander effect, where one activated cell unmasks a cytotoxic molecule and kills cells physically adjacent to the activated cells. Collectively, this work illustrates that the split esterase system is a valuable new addition to the split protein toolbox, with particularly exciting potential in synthetic biology applications.

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Phase II study of irinotecan and amrubicin in patients with relapsed non-small cell lung cancer: Okayama Lung Cancer Study Group Trial 0402

Abstract: Combination chemotherapy with irinotecan and amrubicin is effective in patients with NSCLC but showed moderate toxicities in second- or third-line settings.

Cited by 9 publications

References 20 publications

Development of a Split Esterase for Protein–Protein Interaction-Dependent Small-Molecule Activation

Development of a Split Esterase for Protein–Protein Interaction-Dependent Small-Molecule Activation

Disappearance of an activated EGFR mutation after treatment with EGFR tyrosine kinase inhibitors

Development of a Split Esterase for Protein-Protein Interaction Dependent Small Molecule Activation

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