Metabolic Activation of CPT-11, 7-Ethyl-10-(4-(1-piperidino)-1-piperidino)carbonyloxycamptothecin, a Novel Antitumor Agent, by Carboxylesterase.

Satoh, Takaya; Hosokawa, Masakiyo; Atsumi, Ryo; Suzuki, Wataru; Hakusui, Hideo; Nagai, Eiichi

doi:10.1248/bpb.17.662

Cited by 159 publications

(103 citation statements)

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“…MMR-deficient cells were sensitive to topoisomerase I inhibitors (16)(17)(18)(19), such as irinotecan and camptothecin, which form a covalent bond with topoisomerase I and inhibit the breakage-reunion reaction in DNA replication or translation; they are now available as the major chemotherapeutic drugs for colorectal cancer (20,21). In vivo, irinotecan is converted to its active metabolite, SN-38, in the presence of carboxylesterase (22,23).…”

Section: Introductionmentioning

confidence: 99%

The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks

Tahara

Inoue

Sato

et al. 2014

Molecular Cancer Therapeutics

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Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)-deficient colon cancer cells are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC 50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase-specific doublestrand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage-reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy.

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Section: Introductionmentioning

confidence: 99%

The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks

Tahara

Inoue

Sato

et al. 2014

Molecular Cancer Therapeutics

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“…CPT-11 has also demonstrated anticancer activity against a variety of solid tumors in preclinical and clinical trials. 1,4 CPT-11 is a prodrug, which is enzymatically converted by esterases to SN-38, 5,6 a potent topoisomerase I inhibitor that is thought to have the major role in the antitumor activity of CPT-11. 7 However, a large fraction of SN-38 is further metabolized in the liver by members of the UDP-glucuronosyltransferase 1A family to the inactive glucuronide metabolite (SN-38G).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Huang

Prijovich

et al. 2011

Cancer Gene Ther

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CPT-11 is a clinically important prodrug that requires conversion into the active metabolite SN-38, a potent topoisomerase I poison, for antitumor activity. However, SN-38 is rapidly metabolized to the inactive SN-38 glucuronide (SN-38G) in the liver, which reduces the amount of SN-38 available for killing cancer cells. Here, we investigated if local expression of b-glucuronidase (bG) on cancer cells to catalytically convert SN38G to SN38 could enhance the antitumor activity of CPT-11. bG was tethered on the plasma membrane of three different human cancer cell lines: human colon carcinoma (LS174T), lung adenocarcinoma (CL1-5) and bladder carcinoma (EJ). Surface b-glucuronidase-expressing cells were 20 to 80-fold more sensitive to SN-38G than the parental cells. Intravenous CPT-11 produced significantly greater suppression of CL1-5 and LS174 T tumors that expressed bG as compared with unmodified tumors. Furthermore, an adenoviral vector expressing membrane-tethered bG (Ad.bG) increased the sensitivity of cancer cells to SN-38G even at multiplicity of infections as low as 0.16, indicating bystander killing of non-transduced cancer cells. Importantly, intratumoral injection of Ad.bG significantly enhanced the in vivo antitumor activity of CPT-11 as compared with treatment with CPT-11 or Ad vectors alone. This study shows that Ad.bG has potential to boost the therapeutic index of CPT-11.

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“…For example, the anti-cancer prodrug, CPT-11 (irinotecan), a carbamate derivative of 7-ethyl-10-hydroxycamptothecin, is converted to its active metabolite, 7-ethyl-10-hydroxycamptothecin by human carboxylesterases. The efficiency of hydrolysis varies depending on isoforms such that carboxylesterase 2 (hCE2) 1 and intestinal carboxylesterase (hiCE) are more efficient activators than human liver carboxylesterase 1 (hCE1) (2)(3)(4). The angiotensin-converting enzyme inhibitor temocapril, an ester prodrug, is rapidly hydrolyzed by carboxylesterase to the active temocaprilat.…”

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confidence: 99%

Identification of a Human Valacyclovirase

Kim¹,

Chu²,

Kim³

et al. 2003

Journal of Biological Chemistry

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Valacyclovir is the 5-valyl ester prodrug of acyclovir, an effective anti-herpetic drug. Systemic availability of acyclovir in humans is three to five times higher when administered orally as the prodrug. The increased bioavailability of valacyclovir is attributed to carrier-mediated intestinal absorption, via the hPEPT1 peptide transporter, followed by the rapid and complete conversion to acyclovir. The one or more human enzymes responsible for in vivo activation of the prodrug to the active drug and its conversion sites, however, have not been identified. In this report, we describe the purification, identification, and characterization of a human enzyme that activates valacyclovir to acyclovir. A protein with significant hydrolytic activity toward valacyclovir, the 5-glycyl ester of acyclovir, and the 5-valyl ester of zidovudine (AZT), was purified from Caco-2 cells derived from human intestine. Using a non-redundant data base search, the N-terminal 19-amino acid sequence of the purified 27-kDa, basic protein revealed a perfect match within the N terminus of a serine hydrolase, Biphenyl hydrolase-like (BPHL, gi:4757862) protein, previously cloned from human breast carcinoma. Recombinant BPHL exhibited significant hydrolytic activity for both valacyclovir and valganciclovir with specificity constants (k cat /K m ), 420 and 53.2 mM ؊1 ⅐s ؊1 , respectively. We conclude that BPHL may be an important enzyme activating valacyclovir and valganciclovir in humans and an important new target for prodrug design.Prodrugs of therapeutically active agents have been used to improve pharmaceutical, biopharmaceutical, and pharmacokinetic properties of numerous active therapeutic agents. Prodrugs are designed to be inactive until in vivo activation to the parent drug, and hence reliable in vivo activation of the prodrug is considered critical for their pharmacological activity (1). Identification of the mechanism of in vivo activation of prodrugs is important for prodrug design and for investigating clinical applications. Furthermore, design and development of prodrugs for humans has been significantly hampered by the unknown species differences in the activating enzymes. Thus, identification of the one or more prodrug-activating enzymes will significantly aid in the selection of animal models for human drug development.The participation of peptidases or esterases in prodrug activation will depend on the pro-moiety, its linker to the parent drug, as well as the parent drug. For several prodrugs, their in vivo activation mechanism has been studied in more detail. For example, the anti-cancer prodrug, CPT-11 (irinotecan), a carbamate derivative of 7-ethyl-10-hydroxycamptothecin, is converted to its active metabolite, 7-ethyl-10-hydroxycamptothecin by human carboxylesterases. The efficiency of hydrolysis varies depending on isoforms such that carboxylesterase 2 (hCE2) 1 and intestinal carboxylesterase (hiCE) are more efficient activators than human liver carboxylesterase 1 (hCE1) (2-4). The angiotensin-converting enzyme inhibitor...

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Metabolic Activation of CPT-11, 7-Ethyl-10-(4-(1-piperidino)-1-piperidino)carbonyloxycamptothecin, a Novel Antitumor Agent, by Carboxylesterase.

Cited by 159 publications

References 0 publications

The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks

The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Identification of a Human Valacyclovirase

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