Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-02, Vol.104 (7), p.2074-2079
• Main Authors: Williams, Noelle S, Burgett, Anthony W.G, Atkins, Ashley S, Wang, Xiaodong, Harran, Patrick G, McKnight, Steven L
• Format: Article
• Language: English
• Subjects: Animals; Antimitotics; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Binding sites; Biochemistry; Biological Sciences; Blood; Body Weight - drug effects; Bone marrow; Cancer; Cell division; Chemotherapy; Dosage; Drug Evaluation, Preclinical; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Heterocyclic Compounds, 4 or More Rings - therapeutic use; Medical treatment; Mice; Molecular Mimicry; Neoplasms, Experimental - drug therapy; Neutropenia; Ornithine-Oxo-Acid Transaminase - antagonists & inhibitors; Ornithine-Oxo-Acid Transaminase - physiology; Oxazoles - chemistry; Oxazoles - pharmacology; Oxazoles - therapeutic use; Proteins; Sulfates; Transplantation, Heterologous; Treatment Outcome; Tumors; Vinca
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0611340104

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-δ-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.