CSF-1 AND DRUG RESISTANCE IN REPRODUCTIVE CANCERS

In murine fibroblasts, transfection of the v-FMS oncogenes has been
reported to result in the development of platinum resistance. Although
expression of the FMS (CSF-1 receptor) oncogene has been strongly
correlated with presentations associated with poor prognosis in ovarian
cancer, no link between platinum resistance and expression of this oncogene
has been made in epithelial cancer. Preliminary data suggest that
treatment of epithelial cancer cells that bear the CSF-1 receptor with CSF-
1 may induce this resistance. We and others believe that CSF-1 may act in
epithelial cancer cells in a similar manner to its action in macrophages,
with activation and invasive differentiation being an important components.
It is the purpose of this proposal to further characterize the effects of
CSF-1 treatment on FMS positive cells not only in regards to platinum
resistance, but to its effect on levels of enzymes that scavenge reactive
o2 species (ROS). Macrophage activation is signalled by enhanced oxidative
metabolism, with release of ROS. Elevated glutathione levels is recognized
to be one protective mechanism by which the cells cope with ROS formation,
and is associated with platinum resistance in ovarian cancer. Other ROS
scavenging enzymes have also been induced by similar processes. Thus
measurement of these enzymes will be important in other agents that promote
or interfere with macrophage activation act similarly to CSF-1, or modify
CSF-1's effect on platinum resistance. In order to accomplish these aims
we will transfect epithelial carcinoma cell lines with FMS to study the
effect of ligand binding on sensitivity to platinum. Our long-term
objectives would be to understand the molecular biology underlying platinum
resistance in ovarian cancer and to develop long awaited therapeutics in
this disease.