In vivo pharmacokinetic features, toxicity profile, and chemosensitizing activity of alpha-cyano-beta-hydroxy-beta- methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a novel antileukemic agent targeting Bruton's tyrosine kinase.
The purpose of the present study was to examine the in vivo pharmacokinetics and activity of alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a novel antileukemic agent targeting Bruton's tyrosine kinase (BTK). We have applied an analytical high-performance liquid chromatography method for the quantitative detection of LFM-A13 in plasma samples. Our findings indicate that LFM-A13 is quickly absorbed, with the time required to reach the maximum plasma drug concentration (t(max)) being 10-18 min after i.p. administration with nearly complete bioavailability. LFM-A13 had an elimination half-life of 17-32 min after i.p. administration at dose levels of 10-50 mg/kg. LFM-A13 exhibited a dose-dependent and significant increase in the values of normalized area under the curve and maximum concentration (C(max)) as well as a dose-dependent and significant decrease in clearance values, suggesting a saturable clearance mechanism. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 10 to 80 mg/kg. Highly effective BTK-inhibitory and apoptosis-promoting plasma concentrations of LFM-A13 could be achieved in mice without toxicity. LFM-A13 exhibited a favorable pharmacokinetic behavior that was not adversely affected by the standard chemotherapy drugs vincristine, methylprednisolone, or L-asparaginase (when used as combination treatment, VPL) and significantly improved the chemotherapy response and survival outcome of mice challenged with BCL-1 leukemia cells. Whereas only 14% of mice treated with the standard triple-drug combination VPL became long-term survivors, 41% of mice treated with this combination plus LFM-A13 survived long-term. LFM-A13 prolonged the median survival time of VPL-treated mice from 37 to 58 days. Our results confirm and extend previous studies regarding the role of BTK chemotherapy resistance of B-lineage leukemic cells (S. Mahajan et al., J. Biol. Chem., 274: 9587-9599, 1999). BTK inhibitors such as LFM-A13 may be useful as a new class of chemosensitizing and apoptosis-promoting antileukemic agents for treatment of patients with chemotherapy-resistant B-lineage leukemias or lymphomas.
Uckun
Fatih M
FM
Parker Hughes Cancer Center, Parker Hughes Institute, St. Paul, Minnesota 55113, USA. Faith_Uckun@mercury.ih.org
Zheng
Yaguo
Y
Cetkovic-Cvrlje
Marina
M
Vassilev
Alexei
A
Lisowski
Elizabeth
E
Waurzyniak
Barbara
B
Chen
Hao
H
Carpenter
Randy
R
Chen
Chun-Lin
CL
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019540:Area Under Curve; D001215:Asparaginase / Q000494:pharmacology; D001682:Biological Availability; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008775:Methylprednisolone / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D000577:Amides; D000970:Antineoplastic Agents; C118451:LFM A13; D009570:Nitriles; D014750:Vincristine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D001215:Asparaginase; D008775:Methylprednisolone