| dc.description.abstract | IL-6 is a pleiotropic cytokine that has a significant role in inflammatory processes. In
relation to ovarian cancer biology there is emerging evidence that it mediates
processes relating to tumour growth, invasion, angiogenesis and chemo-resistance that
lead to disease with poor prognosis. The aim of this thesis was to evaluate the efficacy
and mechanism of action of an anti-human IL-6 antibody, CNTO328, in ovarian
cancer. These aims were achieved with a clinical trial that was conducted in parallel
with pre-clinical experiments.
18 patients with advanced platinum-resistant ovarian cancer were treated with
CNTO328 in a phase II clinical trial. One patient had a partial response and seven
patients attained stable disease at the end of the initial 6-week study period with
correlations seen between clinical benefit and baseline levels of CRP, β2-
microglobulin, TNF-α, IL-8 and VEGF. Four patients completed 6 months of
treatment and had significantly decreased plasma CCL2 and increased sgp130
concentrations. Furthermore, immunohistochemical analysis of diagnostic biopsies
suggested that clinical benefit was related to a lower macrophage infiltrate and
increased stromal expression of IL-6, IL-6 receptors and SOCS3.
I have found two ovarian cancer cell lines that secreted IL-6 and expressed both
components of the IL-6 receptor signalling complex. When these cells were grown on
plastic, CNTO328 had no effect on cell proliferation or survival. This suggested that
IL-6 was not a growth factor for ovarian cancer cells in vitro. However, CNTO328
reduced constitutive secretion of IL-6, IL-1β, TNF-α, IL-8 and CCL2 by the ovarian
cancer cells. The in vivo studies with human ovarian cancer xenograft models in nude
mice showed that anti-IL-6 treatment had biological activity by inhibiting cell
proliferation, macrophage infiltration and angiogenesis. In conclusion, the xenograft
models and cell line experiments together with the clinical trial show that IL-6 may be
a therapeutic target in ovarian cancer and exhibits both autocrine and paracrine
actions within the ovarian cancer microenvironment. | en_US |
