Ovarian cancer is one of the significant and deadly disease. Since 1980 when
cisplatin was introduced in the
chemotherapy, about 30% of the patients with advanced disease have achieved 5-year survival. However, remaining patients have had progressive disease or recurrence after achieving NED. Forty-seven% of recurrent disease was discovered as distant
metastasis, while at initial
therapy. In the recurrent disease, distantly metastatic lesions were encountered more frequently than those in primary disease. In the recurrent
tumor, expression of immunohistochemical markers of
malignancy, such as p53
protein and
CD44v6 antigen were increased. These clinical data suggest that recurrent
ovarian cancer which are exposed to
anticancer agents attain increased metastatic potential. In order to assure that
anticancer agent contribute to this increment, an experimental system using two human
ovarian cancer cell lines (HRA, KF) and nude mice in which
cancer cells were exposed to
cisplatin in vivo was introduced.
Cancer cells exposed to
cisplatin in vivo (treated cells) made spontaneously more metastatic nodules in the mouse lung than those exposed to PBS (untreated cells). This result suggest that
cisplatin induce the increase of metastatic potential of
cancer cells in vivo. Treated cells showed higher invasiveness compared with untreated cells when inoculated in the footpad. Three major factors which were generally proposed to be necessary for
cancer cell to give rise to invasion, such as attachment to extracellular matrix, production of
proteolytic enzyme, and cellular mobility. For all of these factors, treated cells were superior to untreated cells. These results obtained suggests that
cisplatin could increase the metastatic potential of
cancer by enhancing potential of invasion. To investigate the mechanism of this phenomenon from the standpoint of genetic mutation, clonal analysis of experimental
cancer in vivo was performed using southern blot method.
Cancer cells before inoculation to the mice consisted of multiple clones. In 5 week after inoculation,
tumor was wholely occupied by only one clone which showed one band on the lane. At this point
cisplatin were administered. In 6 week, new single clone appeared with different band pattern from that of the clone at the administration of
cisplatin. Furthermore, the
cisplatin-induced new clone metastasized to the lung, while no
metastasis was observed in the mouse with PBS-treated
tumor during the same period. These data suggest that increased metastatic potential after
cisplatin treatment is due not to selection but to creation of highly metastatic clone caused by potential of genetic mutation of
cisplatin. In conclusion, chemotherapeutic agent has a potential to create highly malignant
cancer cells as well as a potential to kill
cancer cells.