IFN-beta-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).
By attacking established tumor vasculature, vascular disrupting agents (VDAs) represent an alternative approach to the treatment of cancer. One such VDA, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), is scheduled for phase III trials for prostate and lung cancer in combination with conventional chemotherapies. In this work, we identify interferon-beta (IFN-beta) as a central mediator in the host's response to DMXAA. In mice bearing Lewis lung adenocarcinomas, a single intraperitoneal dose of DMXAA was shown to effect a highly significant reduction in tumor growth rate in wild-type mice that was not seen in IFN-beta-null mice. Moreover, intratumoral cytokine expression was shown to be dependent on host-derived IFN-beta, as DMXAA-treated IFN-beta-null mice demonstrated a lack of induction of not only IFN-beta but also the antiangiogenic cytokine, IP-10, in excised tumor tissue. These results support the conclusion that DMXAA derives its potent anticancer properties in part through elicitation of IFN-beta expression by host-derived elements.
Roberts
Zachary J
ZJ
Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201, USA.
Ching
Lai-Ming
LM
Vogel
Stefanie N
SN
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001808:Blood Vessels / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism*; D005260:Female; D016899:Interferon-beta / Q000276:immunology / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D044004:Xanthones / Q000494:pharmacology
D000970:Antineoplastic Agents; D054357:Chemokine CXCL10; D044004:Xanthones; C066668:vadimezan; D016899:Interferon-beta