title: Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity.
abstract: Blocking cell division through the inhibition of mitosis is one of the most successful clinical strategies for the treatment of cancer. Taxanes and vinca alkaloids are in widespread use and have demonstrated substantive therapeutic efficacy. Both classes of compounds bind directly to tubulin, a structural component of the mitotic spindle. The ubiquitous utilization of tubulin in cell division in both cancerous and normal cells, however, tempers the broad spectrum of activity of currently used antimitotics by significant toxicities in normal dividing tissue. Moreover, peripheral nerve cells that rely on microtubules to shuttle cargo along axonal processes are also damaged by tubulin-binding drugs. Thus, neutropenia and peripheral neuropathy are the most frequently cited dose-limiting toxicities of this class of chemotherapeutics. Here we report the preclinical assessment of AB-5, a structural and functional analog of the natural product diazonamide A. AB-5, like taxanes and vinca alkaloids, blocks cell division during mitosis. However, AB-5 works not by binding tubulin but rather through inhibition of a newly discovered role for ornithine-delta-aminotransferase in mitosis. We hereby report that, unlike other antimitotics, AB-5 is extremely well tolerated by mice when administered under conditions where the drug cures xenografted tumors as effectively as taxanes and vinca alkaloids. AB-5-treated mice show no weight loss, no change in overall physical appearance, and no evidence of neutropenia. These observations raise the possibility that AB-5 may have clinical utility for cancer therapy under conditions largely devoid of chemotherapeutic toxicity and suggest that further preclinical evaluation of AB-5 is warranted.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Anthony W G
authors.initials: AW
authors.lastname: Burgett
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Atkins
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Harran
authors.forename: Steven L
authors.initials: SL
authors.lastname: McKnight
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018716:Molecular Mimicry; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009503:Neutropenia; D009953:Ornithine-Oxo-Acid Transaminase / Q000037:antagonists & inhibitors / Q000502:physiology; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D010080:Oxazoles; C408862:diazonamide A; D009953:Ornithine-Oxo-Acid Transaminase