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Research Articles: Therapeutics, Targets, and Development

Nonimmunosuppressive chemotherapy: EM011-treated mice mount normal T-cell responses to an acute lymphocytic choriomeningitis virus infection

¹ Laboratory for Drug Discovery, Design, and Research, Department of Cell Biology, and ² Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Ritu Aneja or Harish C. Joshi, Laboratory for Drug Discovery, Design, and Research, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322. Phone: 404-727-0445. E-mail: raneja{at}emory.edu or joshi{at}cellbio.emory.edu

Abstract

Myelosuppression and associated immunosuppression are major problems in cancer chemotherapy. Thus, infection remains a significant source of morbidity and mortality during chemotherapy of cancer patients. Viral infections, particularly herpes simplex virus, varicella zoster virus, and cytomegalovirus, result either due to reactivation of latent viruses or new infections as sequelae of chemotherapy and debilitated cell-mediated immunity. Ultimately, the resolution of these infections can only be achieved after the control of malignancy and regaining the patient's ability to mount adequate immune responses. We show here that EM011, a tubulin-binding, nontoxic, orally available anticancer agent, does not alter absolute CD4⁺, CD8⁺, B220⁺, and NK1.1⁺ cell counts in immunocompetent mice. More importantly, EM011 treatment at tumor-suppressive dosages (300 mg/kg) does not suppress cell-mediated immune responses in mice experimentally challenged with acute lymphocytic choriomeningitis virus infection, in that mice mount robust virus-specific CD8⁺ and CD4⁺ T-cell immune responses while maintained on daily drug treatment. Thus, CD8⁺ and CD4⁺ T-cell expansion and acquisition of effector functions is not perturbed by EM011 treatment. These data provide compelling evidence to support the nonimmunosuppressive nature of EM011 therapy and provide strong impetus for combining chemotherapy with immunotherapy as a novel anticancer strategy. [Mol Cancer Ther 2007;6(11):2891–9]

Grant support: NIH grant R01 CA095317 (H.C. Joshi).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/25/07; revised 8/14/07; accepted 9/20/07.