title: A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled in this study with 42 cycles being administered over seven dose levels (50-350 mg/day). Two patients experienced DLTs related to tigecycline at the 350 mg/day level resulting in a maximal tolerated dose of tigecycline of 300 mg as a once daily infusion. Pharmacokinetic experiments showed that tigecycline had a markedly shorter half-life in these patients than reported for noncancer patients. No significant pharmacodynamic changes or clinical responses were observed. Thus, we have defined the safety of once daily tigecycline in patients with refractory AML. Future studies should focus on schedules of the drug that permit more sustained target inhibition.
authors.affiliation: University of Kansas Cancer Center, Kansas City, Kansas.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Reed
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schiller
authors.affiliation: University of Kansas Cancer Center, Kansas City, Kansas.
authors.forename: Suman
authors.initials: S
authors.lastname: Kambhampati
authors.affiliation: Leukemia Service, Department of Medicine, Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Leukemia Service, Department of Medicine, Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Dan
authors.initials: D
authors.lastname: Douer
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Yee
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brandwein
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Jitkova
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Aisha
authors.initials: A
authors.lastname: Shamas-Din
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Andre C
authors.initials: AC
authors.lastname: Schuh
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008911:Minocycline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D012008:Recurrence; D019233:Retreatment; D018570:Risk Assessment; D000078304:Tigecycline; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D000078304:Tigecycline; D008911:Minocycline
keywords: Cox-1; Cox-4; mitochondrial protein synthesis; pharmacodynamics; pharmacokinetics