title: Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species.
abstract: Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose-dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0-2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed-onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers.
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61802, USA.|Carle R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Alycen P
authors.initials: AP
authors.lastname: Lundberg
authors.affiliation: Carle R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.|Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Francis
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61802, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Pajak
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Parkinson
authors.affiliation: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61802, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Wycislo
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.affiliation: Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Brown
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: London
authors.affiliation: Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA.
authors.forename: Levent
authors.initials: L
authors.lastname: Dirikolu
authors.affiliation: Carle R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.|Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61802, USA. t-fan@illinois.edu.|Carle R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. t-fan@illinois.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000378:metabolism; D002415:Cats; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D009062:Mouth Neoplasms / Q000097:blood / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D011809:Quinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011809:Quinones; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016660:NAD(P)H Dehydrogenase (Quinone); D003849:Deoxyguanosine
keywords: Comparative oncology; Deoxynyboquinone; Feline oral squamous cell carcinoma; NQO1; Novel anti-cancer agent; β-lapachone