An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11

Cancer Gene Therapy
Monika WierdlPhilip M Potter

Abstract

CPT-11 is a potent antitumor agent that is activated by carboxylesterases (CE) and intracellular expression of CEs that can activate the drug results in increased cytotoxicity to the drug. As activation of CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) by human CEs is relatively inefficient, we have developed enzyme/prodrug therapy approaches based on the CE/CPT-11 combination using a rabbit liver CE (rCE). However, the in vivo application of this technology may be hampered by the development of an immune response to rCE. Therefore, we have developed a mutant human CE (hCE1m6), based on the human liver CE hCE1, that can activate CPT-11 approximately 70-fold more efficiently than the wild-type protein and can be expressed at high levels in mammalian cells. Indeed, adenoviral-mediated delivery of hCE1m6 with human tumor cells resulted in up to a 670-fold reduction in the IC(50) value for CPT-11, as compared to cells transduced with vector control virus. Furthermore, xenograft studies with human tumors expressing hCE1m6 confirm the ability of this enzyme to activate CPT-11 in vivo and induce antitumor activity. We propose that this enzyme should likely be less immunogenic than rCE and would b...Continue Reading

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Citations

Jan 5, 2013·Journal of Natural Products·M Jason HatfieldPhilip M Potter
Mar 29, 2008·Gene Therapy·K S AboodyM K Danks
Mar 30, 2011·PloS One·Andrew C HemmertMatthew R Redinbo
Jan 21, 2014·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Fang-Wei XieXue-Nong Ouyang
Jan 1, 2010·Journal of Pest Science·Shana V StoddardRandy M Wadkins
Feb 20, 2016·Chemico-biological Interactions·M Jason HatfieldPhilip M Potter
Aug 30, 2008·Expert Opinion on Drug Metabolism & Toxicology·Jason M HatfieldPhilip M Potter
Dec 9, 2008·Clinics in Laboratory Medicine·Alicia Algeciras-SchimnichChristine L H Snozek
Jul 24, 2010·British Journal of Pharmacology·M J HatfieldP M Potter
Jul 17, 2016·British Journal of Pharmacology·Monika WierdlPhilip M Potter
Jan 4, 2017·Current Pharmacology Reports·Obeid M MalekshahArash Hatefi
Jul 12, 2018·Molecular Therapy. Methods & Clinical Development·Revathiswari TirughanaKaren S Aboody
May 20, 2021·CNS Oncology·Anda-Alexandra CalinescuSue K O'Shea
Jun 27, 2021·Chemico-biological Interactions·Yun-Qing SongGuang-Bo Ge
Feb 23, 2020·Journal of Agricultural and Food Chemistry·R Domínguez-PerlesA Gil-Izquierdo
Dec 19, 2020·Current Drug Metabolism·Steven X HuKenneth L Feenstra

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