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Review
. 2008 Apr;99(4):653-8.
doi: 10.1111/j.1349-7006.2008.00747.x.

Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma

Affiliations
Review

Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma

Hiroaki Itamochi et al. Cancer Sci. 2008 Apr.

Abstract

Clear cell carcinoma (CCC) accounts for 4% to 12% of epithelial ovarian cancer in Western countries and, for some unknown reasons, it comprises more than 20% of such cancers in Japan. CCC shows unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of vascular thromboembolic complications, and hypercalcemia. It is frequently associated with endometriosis. Compared to serous adenocarcinoma (SAC), CCC is relatively resistant to conventional platinum, or taxane-based chemotherapy which is associated with its poor prognosis. However, the mechanisms underlying CCC's resistance to chemotherapy have not been understood. Although several mechanisms involved in drug resistance exist in CCC, including decreased drug accumulation, increased drug detoxification, and an increased DNA repair activity; however, no particular chemoresistance system has been identified. On the other hand, an in vitro study revealed that low cell proliferation may cause the insensitivity of CCC to cisplatin. The Ki-67 labeling index in CCC tumors was significantly lower than SAC. The Ki-67 labeling index for responders was significantly higher than that for non-responders in both tumor types. A multivariable analysis revealed that Ki-67 labeling index and residual tumor size were independent prognostic factors in CCC. Therefore, lower proliferation of the tumor cells may contribute to their resistance to chemotherapy. However, further investigation into the molecular biology and genetics of CCC is warranted. This review discusses the current state of knowledge of the chemoresistance mechanism in CCC and novel treatment strategies for CCC.

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Figures

Figure 1
Figure 1
Mechanisms of drug resistance. ABC transporter; ATP‐binding cassette transporter; EGFR, epidermal growth‐factor receptor; GSH, glutathione; GST‐π, glutathione S‐transferase‐π; HER2, v‐erb‐b2 erythroblastic leukemia viral oncogene homolog 2; NMR, nucleotide excision repair; MMR, DNA mismatch repair.
Figure 2
Figure 2
The phase of the cell cycle and its regulation. Proliferation depends on the ability of the cell to successfully pass through the G1, S, G2, and M phases of the cell cycle. Such cell progression is controlled by cyclin‐dependent kinases (CDKs), which themselves are regulated by cyclin binding, phosphorylation, and CDK inhibitors. The quiescence state is called G0 phase. There are two known CDK inhibitor families, p21Cip1/WAF1 and p27Kip1 inhibit CDK2 and p16INK4a inhibits CDK4 and –6.
Figure 3
Figure 3
Correlation between the S‐phase fraction (SPF) and the IC50 to cisplatin (CDDP) in the clear cell carcinoma cell lines. There was a significant reverse correlation between the SPF and the IC50 to CDDP.
Figure 4
Figure 4
Histograms of the Ki‐67 labeling index for clear cell carcinoma and serous adenocarcinoma. The Ki‐67 labeling index for clear cell carcinoma was significantly lower than that for serous adenocarcinoma (mean ± standard deviation, 18.4 ± 9.9 vs 38.8 ± 15.0%; P < 0.01).

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