Pharmacology of EAPB0203, a novel imidazo[1,2-a]quinoxaline derivative with anti-tumoral activity on melanoma.
In spite of the development of new anticancer drugs by the pharmaceutical industry, melanoma and T lymphomas are diseases for which medical advances remain limited. Thus, there was an urgent need of new therapeutics with an original mechanism of action. Since several years, our group develops quinoxalinic compounds. In this paper, the first preclinical results concerning one lead compound, EAPB0203, are presented. This compound exhibits in vitro cytotoxic activity on A375 and M4Be human melanoma cell lines superior to that of imiquimod and fotemustine. A liquid chromatography-mass spectrometry method was first validated to simultaneously quantify EAPB0203 and its metabolite, EAPB0202, in rat plasma. Thereafter, the pharmacokinetic profiles of EAPB0203 were studied in rat after intravenous and intraperitoneal administrations. After intraperitoneal administration the absolute bioavailability remains limited (22.7%). In xenografted mouse, after intraperitoneal administration of 5 and 20mg/kg, EAPB0203 is more potent than fotemustine. The survival time was increased up to 4 and 2 weeks compared to control mice and mice treated by fotemustine, respectively. The results of this study demonstrate the relationship between the dose of EAPB0203 and its effects on tumor growth. Thus, promising efficacy, tolerance and pharmacokinetic data of EAPB0203 encourage the development towards patient benefit.
Clinical Pharmacokinetic Laboratory, EA4215, Faculty of Pharmacy, University Montpellier I, B.P. 14491, 34093 Montpellier Cedex 5, France. FBressolle@aol.com
Sonia
S
Khier
Carine
C
Deleuze-Masquéfa
Georges
G
Moarbess
Florence
F
Gattacceca
Delphine
D
Margout
Isabelle
I
Solassol
Jean-François
JF
Cooper
Frédéric
F
Pinguet
Pierre-Antoine
PA
Bonnet
Françoise M M
FM
Bressolle
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics; D000077271:Imiquimod; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009607:Nitrosourea Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011810:Quinoxalines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012878:Skin Neoplasms / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays
C548992:1-(2-phenethyl)imidazo(1,2-a)quinoxalin-4-amine; D000634:Aminoquinolines; D000970:Antineoplastic Agents; C528810:EAPB0203; D007093:Imidazoles; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D011810:Quinoxalines; C054368:fotemustine; D000077271:Imiquimod