Circadian pharmacology of L-alanosine (SDX-102) in mice.
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 characterized small intestinal MTAP expression with a maximum at 6:30 hours after light onset (P = 0.04). A minor survival improvement was found in MTAP-deficient P388 mice receiving SDX-102 at 7 or 23 hours after light onset as compared with other times (P = 0.03, log-rank test). In conclusion, the therapeutic index of SDX-102 was improved by the delivery of SDX-102 in the mid to late activity span. These results support the concept of chronomodulated infusion of SDX-102 in cancer patients.
Li
Xiao-Mei
XM
Institut National de la Sante et de la Recherche Medicale, U776 "Rythmes biologiques et cancers" (Université Paris Sud), Paul Brousse Hospital, 94800 Villejuif, France.
Kanekal
Sarath
S
Crépin
Delphine
D
Guettier
Catherine
C
Carrière
Jennifer
J
Elliott
Gary
G
Lévi
Francis
F
D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology; D019454:Chronotherapy; D003624:Darkness; D015870:Gene Expression; D006470:Hemorrhage / Q000139:chemically induced; D007422:Intestines / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007941:Leukemia P388 / Q000188:drug therapy*; D008027:Light; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced; D011683:Purine-Nucleoside Phosphorylase / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C000082:alanosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000409:Alanine