Circadian pharmacology of L-alanosine (SDX-102) in mice

Molecular Cancer Therapeutics
XiaoMei LiF Lévi

Abstract

L-alanosine (SDX-102) exerts its cytotoxicity through inhibition of de novo purine biosynthesis, an effect potentiated by methylthioadenosine phosphorylase (MTAP) deficiency. The relevance of circadian dosing time was investigated for chronotherapeutic optimization of SDX-102. Toxicity was assessed in healthy mice following single (1,150, 1,650, or 1,850 mg/kg/d) or multiple doses (250 or 270 mg/kg/d). Efficacy was tested in mice with P388 leukemia receiving multiple doses (225 or 250 mg/kg/d). SDX-102 was administered at six circadian times 4 hours apart in mice synchronized with 12 hours of light alternating with 12 hours of darkness. MTAP expression was determined in liver, bone marrow, small intestinal mucosa, and P388 cells. Dosing at 19 hours after light onset reduced lethality 5-fold after single administration and 3-fold after multiple doses as compared with worst time [P < 0.001 and P < 0.01, respectively (chi2 test)]. Neutropenia, lymphopenia, and bone marrow hemorrhagic lesions were significantly less in mice dosed at 19 hours after light onset as compared with 7 hours after light onset. SDX-102 at 7 hours after light onset transiently ablated the 24-hour patterns in body temperature and activity. A circadian rhythm ...Continue Reading

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Citations

Jan 11, 2007·Annual Review of Pharmacology and Toxicology·Francis Levi, Ueli Schibler
Jan 9, 2010·Annual Review of Pharmacology and Toxicology·Francis LéviJean Clairambault
Feb 19, 2013·Toxicology and Applied Pharmacology·Katrina M WatersThomas J Weber
Dec 2, 2008·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Atilla AltinokAlbert Goldbeter
Aug 19, 2007·Advanced Drug Delivery Reviews·Francis LéviSylvie Giacchetti
Jun 11, 2014·Annals of Medicine·Pasquale F InnominatoFrancis A Lévi
Oct 19, 2017·International Journal of Molecular Sciences·Narin OzturkAlper Okyar
Apr 25, 2006·Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society·Sherri S SchultzPaul A Lucas

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