Intracellular conversion of irinotecan to its active form, SN-38, by native carboxylesterase in human non-small cell lung cancer

Ohtsuka, K; Inoue, Shoichi; Kameyama, Masayo; Kanetoshi, Akio; Fujimoto, Toru; Takaoka, Kazuo; Araya, Yoshikazu; Shida, Akira

doi:10.1016/s0169-5002(03)00223-x

Cited by 57 publications

(36 citation statements)

References 26 publications

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“…A second factor contributing to the enhanced antitumor efficacy of EZN-2208 is PEGylation at the C20 position of SN38 (within the lactone ring) that has been shown for other camptothecins to stabilize the lactone ring (21). Because the closed lactone ring is the active form of SN38 (16,22), and metabolism of CPT-11 creates an open lactone ring that is less tumoricidal, PEGylation should increase the residence time of the closed lactone ring and increase efficacy compared with CPT-11.…”

Section: Discussionmentioning

confidence: 99%

Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model

Sapra

Zhao

Mehlig

et al. 2008

Clinical Cancer Research

159

148

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Purpose: Clinical development of SN38, the active metabolite of camptothecin-11 (CPT-11), has been hampered due to its poor solubility. We have developed a novel polymer-drug conjugate, EZN-2208, made by linking SN38 with a multiarm polyethylene glycol via a glycine linker. Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. The therapeutic efficacy of EZN-2208 was evaluated in various xenografts, including an in vivoŝ elected CPT-11^refractory model. Tumor and blood concentration of EZN-2208, CPT-11, and SN38 was determined by high-performance liquid chromatography.Results: In vitro, EZN-2208 was 10-to 245-fold more potent than CPT-11in a panel of human tumor cell lines. In xenograft models of MX-1 breast, MiaPaCa-2 pancreatic, or HT-29 colon carcinoma, treatment with either a single dose or multiple injections of EZN-2208 was more efficacious (and in some cases produced tumor eradication for >16 weeks) compared with CPT-11 at their respective maximum tolerated doses or corresponding dose levels (P < 0.01).Most interestingly, EZN-2208 showed marked antitumor activity in animals that developed resistance to an 8-day course of CPT-11 treatment, as well as outperformed CPT-11 as secondround therapy in mice initially sensitive to CPT-11. EZN-2208 had prolonged circulation in the blood compared with CPT-11, resulting in high tumor exposure. This resulted in higher and longer-lasting tumor exposure of free SN38 in mice given EZN-2208 compared with those given CPT-11. Conclusions: Preclinical data suggest that EZN-2208 may be a promising anticancer agent in a wide variety of clinical settings, including tumors refractory to CPT-11treatment.

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Section: Discussionmentioning

confidence: 99%

Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model

Sapra

Zhao

Mehlig

et al. 2008

Clinical Cancer Research

159

148

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“…Some tumors are reported to express CES2 but not necessarily uniformly throughout the tumor (31)(32)(33). To test whether neighboring CES2-expressing cells may alter growth of cells devoid of CES2, HCT-116 transfectants and fluorescent GFP-tagged PC-3 cells were grown individually or cocultured together.…”

Section: Bystander Effectmentioning

confidence: 99%

Human Carboxylesterase-2 Hydrolyzes the Prodrug of Gemcitabine (LY2334737) and Confers Prodrug Sensitivity to Cancer Cells

Pratt

Durland-Busbice

Shepard

et al. 2013

Clinical Cancer Research

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Purpose: The oral prodrug of gemcitabine LY2334737 is cleaved systemically to gemcitabine; the mechanism responsible for hydrolysis is unknown. LY2334737 cytotoxicity was tested in the NCI-60 panel; mining of microarray expression data identified carboxylesterase (CES) as a top hydrolase candidate. Studies examined whether CES is responsible for hydrolysis and whether cellular CES expression confers prodrug sensitivity.Experimental Design: Human recombinant CES isozymes were assayed for LY2334737 hydrolysis. Stable CES-overexpressing HCT-116 transfectants and a SK-OV-3 knockdown were prepared. Cell lines were tested for drug sensitivity and CES expression by quantitative real time-PCR (qRT-PCR), Western blotting, and immunohistochemical staining. Bystander cytotoxicity studies were conducted with GFP-tagged PC-3 cells as the reporter cell line. Therapeutic response of the HCT-116 transfectants was evaluated in xenografts.Results: Of 3 human CES isozymes tested, only CES2 hydrolyzed LY2334737. Five cell lines that express CES2 responded to LY2334737 treatment. LY2334737 was less cytotoxic to a SK-OV-3 CES2 knockdown than parental cells. The drug response of CES2-transfected HCT-116 cells correlated with CES2 expression level. Bystander studies showed statistically greater PC-3-GFP growth inhibition by LY2334737 when cells were cocultured with CES2 and not mock transfectants. Oral treatment of xenograft models with 3.2 mg/kg LY2334737 once a day for 21 days showed greater tumor growth inhibition of CES2 transfectant than the mock transfectant (P 0.001).Conclusions: CES2 is responsible for the slow hydrolysis of LY2334737. Because intact prodrug circulates at high plasma levels after oral LY2334737 administration, improved response rates may be observed by tailoring LY2334737 treatment to patients with CES2 tumor expression.

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“…Actually, it has been shown that dog CES1 isozyme was involved in a pulmonary first-pass effect in the disposition of a propranolol ester prodrug (Imai, 2006;Imai et al, 2006). It has also been shown that the expression level of the human CarbE isozyme was correlated with the conversion ratio of CPT-11 to SN-38, the active metabolite, which is thought to be a key step for the chemotherapeutic action of this anti-tumor drug (Pindel et al, 1997;Zhang et al, 2002;Ohtsuka et al, 2003;Sanghani et al, 2003).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Carboxylesterases: Structure, Function and Polymorphism

Satoh¹,

Hosokawa²

2009

Biomolecules and Therapeutics

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-This review covers current developments in molecular-based studies of the structure and function of carboxylesterases. To allay the confusion of the classic classification of carboxylesterase isozymes, we have proposed a novel nomenclature and classification of mammalian carboxylesterases on the basis of molecular properties. In addition, mechanisms of regulation of gene expression of carboxylesterases by xenobiotics, and involvement of carboxylesterase in drug metabolism are also described.

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Intracellular conversion of irinotecan to its active form, SN-38, by native carboxylesterase in human non-small cell lung cancer

Cited by 57 publications

References 26 publications

Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model

Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model

Human Carboxylesterase-2 Hydrolyzes the Prodrug of Gemcitabine (LY2334737) and Confers Prodrug Sensitivity to Cancer Cells

Carboxylesterases: Structure, Function and Polymorphism

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