dc.contributor.author |
Ching, Lai-Ming |
en |
dc.contributor.author |
Henare, Kimiora |
en |
dc.contributor.author |
Tijono, Sofian |
en |
dc.contributor.author |
Tomek, Petr |
en |
dc.coverage.spatial |
Tauranga, New Zealand |
en |
dc.date.accessioned |
2015-04-15T03:10:15Z |
en |
dc.date.issued |
2014-10-21 |
en |
dc.identifier.citation |
New Zealand Society for Oncology Conference: Oncology in New Zealand; current and future challenges, Tauranga, New Zealand, 21 Oct 2014 - 23 Oct 2014. 21 Oct 2014 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/25223 |
en |
dc.description.abstract |
DMXAA (5,6-dimethylxanthenone-4-acetic acid), developed at the ACSRC, entered human clinical trials based on its excellent curative activity against a range of preclinical tumours in mice. Phase 2 clinical trials were promising, but phase 3 trials in combination with chemotherapy failed to show survival benefit against lung cancer compared to chemotherapy alone. The reason for DMXAA’s failure in phase 3 has been hotly debated. As part of our efforts to elucidate the basis of its inter-species differences, we showed that DMXAA has a diminished capacity to stimulate cytokine production in cultured human leucocytes compared to that in murine leucocytes. Moreover, we identified XAA analogues that showed superior activity to DMXAA in stimulating IL-8, IL-6 and TNF- production by human leucocytes. These ‘human-selective’ analogues did not stimulate cytokine production in mouse cells however. The molecular mechanisms underlying DMXAA’s cytokine-inducing/immune-modulatory activity, a key component of DMXAA’s durable antitumour activity in mice, has yet to be fully elucidated. The NF-κB pathway, the stimulator of interferon genes (STING) and TBK1-IRF-3 signaling axis, the NOD signaling pathways, and at least 3 members of the MAPK superfamily and redox signaling have all been implicated. Recent studies showed that activation of STING in murine macrophages appears essential for DMXAA-induced IFN- production. Despite 89% structural similarity in the two homologues, DMXAA binds murine STING but not human STING, and DMXAA does not stimulate IFN-production in human monocytic/macrophage cell lines. Preliminary studies suggest that the human-selective XAA analogues do not bind to either murine or human STING, and nor do they induce IFN-in murine or humanmonocytic/macrophage lines in culture. IL-8 is the most abundantly produced cytokine in human peripheral blood leucocyte cultures, and the production of this cytokine is not dependent on STING activation. The NOD homologues may exhibit less species-specificity, as DMXAA has been shown to activate human NOD 2. Studies are underway to determine if the human-active XAA analogues stimulate IL-8 production through NOD-dependent pathways. |
en |
dc.relation.ispartof |
New Zealand Society for Oncology Conference: Oncology in New Zealand; current and future challenges |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
The role of two NODs and a STING in the tale of DMXAA |
en |
dc.type |
Conference Item |
en |
dc.description.version |
Abstract |
en |
pubs.finish-date |
2014-10-23 |
en |
pubs.start-date |
2014-10-21 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Abstract |
en |
pubs.elements-id |
461141 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Te Kupenga Hauora Maori |
en |
pubs.org-id |
TKHM Teaching |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2014-11-17 |
en |