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

Summary 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..

Medienart:

E-Artikel

Erscheinungsjahr:

2016

Erschienen:

2016

Enthalten in:

Zur Gesamtaufnahme - volume:35

Enthalten in:

Investigational new drugs - 35(2016), 2 vom: 14. Dez., Seite 134-144

Sprache:

Englisch

Beteiligte Personen:

Lundberg, Alycen P. [VerfasserIn]
Francis, Joshua M. [VerfasserIn]
Pajak, Malgorzata [VerfasserIn]
Parkinson, Elizabeth I. [VerfasserIn]
Wycislo, Kathryn L. [VerfasserIn]
Rosol, Thomas J. [VerfasserIn]
Brown, Megan E. [VerfasserIn]
London, Cheryl A. [VerfasserIn]
Dirikolu, Levent [VerfasserIn]
Hergenrother, Paul J. [VerfasserIn]
Fan, Timothy M. [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

BKL:

44.40$jPharmazie$jPharmazeutika

Themen:

β-lapachone
Comparative oncology
Deoxynyboquinone
Feline oral squamous cell carcinoma
NQO1
Novel anti-cancer agent

Anmerkungen:

© Springer Science+Business Media New York 2016

doi:

10.1007/s10637-016-0414-z

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2112999648

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