HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes.

Abstract
5,6-Di-methylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity. Although classified as a "vascular disrupting agent," we have recently conducted studies showing that DMXAA has remarkable efficacy in a range of tumors, working primarily as an immune modulator that activates tumor-associated macrophages and induces a subsequent CD8(+) T-cell-mediated response. To more completely analyze the effect of DMXAA on CD8(+) T-cell generation, we treated mice bearing tumors derived from EG7 thymoma cells that express the well-characterized chicken ovalbumin neotumor antigen. Treatment with DMXAA led to cytokine release, tumor cell necrosis, and ultimately reduction in tumor size that was lymphocyte dependent. Within 24 h of administration, we observed dendritic cell activation in tumor-draining lymph nodes (TDLN). This was followed by a rapid and marked increase in the number of tetramer-specific CD8(+) T cells in the spleens of treated animals. In contrast, the vascular disrupting agent combretastatin A4-phosphate, which caused a similar amount of immediate tumor necrosis, did not activate dendritic cells, nor induce an effective antitumor response. Using in vitro systems, we made the observation that DMXAA has the ability to directly activate mouse dendritic cells, as measured by increased expression of costimulatory molecules and proinflammatory cytokine release via a pathway that does not require the Toll-like receptor adaptor molecule MyD88. DMXAA thus has the ability to activate tumor-specific CD8(+) T cells through multiple pathways that include induction of tumor cell death, release of stimulatory cytokines, and direct activation of dendritic cells.
AuthorsAfrica Wallace, David F LaRosa, Veena Kapoor, Jing Sun, Guanjun Cheng, Arminder Jassar, Aaron Blouin, Lai-Ming Ching, Steven M Albelda
JournalCancer research (Cancer Res) Vol. 67 Issue 14 Pg. 7011-9 (Jul 15 2007) ISSN: 0008-5472 [Print] United States
PMID17638914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents
  • Cytokines
  • Myeloid Differentiation Factor 88
  • Xanthones
  • vadimezan
  • Ovalbumin
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • CD8-Positive T-Lymphocytes (metabolism)
  • Cell Line, Tumor
  • Chickens
  • Cytokines (metabolism)
  • Dendritic Cells (cytology, drug effects)
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 (metabolism)
  • Necrosis
  • Neoplasm Transplantation
  • Ovalbumin (metabolism)
  • T-Lymphocytes, Cytotoxic (metabolism)
  • Xanthones (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: