New strategy for overcoming resistance to chemotherapy of ovarian cancer

Abstract

Background: Ovarian cancer is one of the most sensitive solid tumors, with objective responses ranging from 60 to 80% even in patients with advanced stage. However, most patients ultimately recur and develop resistance to chemotherapy. As a result, the survival rate for patients with ovarian cancer has not improved over the past 20 years. Resistance to chemotherapy presents a major obstacle to attempt to improve the prognosis of patients with ovarian cancer. A new strategy is necessary to improve the prognosis of patients with ovarian cancer.

Methods: The mechanism of chemoresistance was reviewed to get over the resistance. Additionally, the biological characteristics of ovarian cancer and molecular-targeted agents including signal-transduction inhibitors and anti-angiogenesis were discussed.

Results: Genetic diagnosis for chemosensitivity with drug-resistance genes may be a useful predictor. Unfortunately, molecular-targeted therapy alone has been insufficient to improve the prognosis for patients with advanced ovarian cancer. Molecular molecular-targeted therapy should be carried out together with conventional cytotoxic agents. On the occasion of the use of the molecular targeted-agents, care of the appearance of the unexpected adverse effect should be important.

Conclusion: The future research in this field will enable to develop an effective strategy for conquest of chemoresistance in ovarian cancer.

Keywords: chemotherapy;; molecular targeted agent; ovarian cancer; resistance.

Fig. 1

Many mechanisms of anticancer agents have been proposed, including decreased drug accumulation, increased cellar detoxification by proteins such as glutathione, decreased the induction of apoptosis and increased DNA repair. GCS, glutamylcysteine synthetase; GSH, glutathione; MDR-l, multidrug-resistance-1; MRP, multidrug resistance-associated protein.

Fig. 2

Isobolograms of cisplatin (CDDP) at IC50, based on dose response curves in combination with SN-38 in KF and KFr cell lines. The abscissa shows the ratio of concentration to the IC50 for CDDP, and the ordinate represents that for SN-38. The solid line represents mode I, and the two broken lines represent mode II. The exposure of CDDP combined with SN-38 to KF cells produces only additive effects. In contrast, for KFr cells the combination of CDDP and SN-38 is synergistic. IC50, half maximal inhibitory concentration; KFr, cisplatin-resistant KF.

Fig. 3

Topo I catalytic activity in KF and KFr cells. Topo I catalytic activity in KFr cells is 4-fold of that in KF cells. KFr, cisplatin-resistant KF; topo, topoisomerase.

Fig. 4

The amount of the extraction is significantly greater in nonresponders than in responders (201.7 ± 92.5 versus 124.1 ± 59.4 ng).

Fig. 5

The receiver operating characteristic (ROC) curve according to chemoresponse for TC (A), EP (B) and CPT-11/CDDP therapy (C). The optimal cut points are 80 for MDR-1, 90 for topo IIalpha and 200 for topo I by selecting the point on the ROC curve that maximized both sensitivity and specificity. CDDP, cisplatin; CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin; EP, combination with etoposide and CDDP; MDR-1, multidrug-resistance-1; TC, combination with paclitaxel and carboplatin; topo, topoisomerase.

Fig. 6

The effects of paclitaxel (PTX) combined with mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3'-kinase (PI3K) inhibitors on ovarian cancer cells. Cell proliferation was significantly suppressed by PTX combined with MEK and PI3K inhibitors compared with other treatment conditions. LY294002, PI3K inhibitor; PD98059, MEK inhibitor.