[Clinical value of human papillomavirus genotyping testing in the diagnosis of cervical intraepithelial neoplasia].

OBJECTIVE: To Investigate the value of HPV genotyping in diagnosis of cervical intraepithelial neoplasia (CIN). METHODS: From July 2012 to February 2013, 200 women from Tianjin Medical University General Hospital and 244 women from Affiliated Hospital of the Chinese People's Armed Forces Logistics College were selected to be HPV genotyping test and thin liqid-based cytology test. Consequently, 132 samples were performed colposcopy test and cervical biopsy. RESULTS: HPV prevalence was 26.4% (117/444) in this study. The infection of one type HPV was more common. The top 5 of HPV types were HPV16, 58, 33, 18, and 52. The top 5 of the risk for CIN II and above followed HPV16, 33, 39, 52 and 18. There was no significant difference between age and HPV positive rate (χ² = 0.948, P > 0.05). Multiple infection and cervical lesions rank correlation analysis (r = 0.132, P > 0.05). For CIN II and above disease, cytology positive rate was 90% (44/49), and HPV positive rate was 96% (47/49)cytology combine HPV positive rate was 98% (48/49, χ² = 0.063, P > 0.05). CONCLUSIONS: HPV infection should increasing trends with age. Cytology test and HPV genotyping test had good consistency. The combination of them can improve the sensitivity for high-grade lesions.

Prognostic value of E-cadherin expression and CDH1 promoter methylation in patients with endometrial carcinoma.

The primary aim of this study is to evaluate the clinical significance of E-cadherin protein expression and the methylation status in CDH1 promoter in endometrial cancer. The expression of E-cadherin and methylation in its promoter region was analyzed, retrospectively, in 152 clinical tissue samples from patients with endometrial lesions. We found that the hypermethylation of CDH1 promoter, which caused low expression of E-cadherin in endometrial cancer, was associated with not only clinicopathological progress of endometrial cancer but also with the overall 5-year clinical survival rate. The findings provide the potential therapeutic and prognostic target molecule for patients with endomethrial cancer.

Identification of cervical cancer proteins associated with treatment with paclitaxel and cisplatin in patients.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) with paclitaxel (T) and cisplatin (P) was commonly used for the treatment of cervical cancer. However, little is known about the antineoplastic mechanism of NAC with TP in patient tissues in situ. In this study, we compared the proteomic profiles of cervical cancer in patients before and after NAC with TP to identify proteins that may shed light on the mechanism of TP action. METHODS: We collected cervical cancer tissues pre- and post-NAC with TP from 6 patients with local advanced cervical cancer and stored them at -80°C. Proteomes of 2 groups of cervical cancer tissues were analyzed by 2-dimensional gel electrophoresis and the differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. Some proteins that are differentially expressed were confirmed by Western blot. RESULTS: There were 13 proteins whose levels were significantly altered after NAC with TP. Compared with pre-NAC, 11 proteins were down-regulated, and 2 proteins were up-regulated in the post-NAC group. The down-regulated proteins were aldolase A, pyruvate kinase, enolase 1, heat shock protein 27 (HSP27), HSP70, actinin α1, lamin B1, eukaryotic translation elongation factor 1γ, annexin 1, epithelial cell marker protein1, keratin II-type. In contrast, apolipoprotein A1 and annexin V were up-regulated. The down-regulation of HSP27, HSP70, enolase 1, and aldolase A was verified by Western blot. CONCLUSIONS: Differentially expressed proteins between cervical cancer tissues pre- and post-NAC with TP were identified by comparative proteomic approach. The NAC therapy with TP down-regulated proteins involved in energy production (glycolytic enzymes) and chaperones but up-regulated proteins involved in apoptosis. These findings shed new light on biomarkers associated with effect of chemotherapy.

[Human endostatin antiangiogenic gene therapy mediated by recombinant adeno-associated virus vector in nude mouse with endometriosis].

OBJECTIVE: To study the therapeutic effect of recombinant adeno-associated virus carrying human endostatin gene therapy on endometriosis in mice model. METHODS: Recombinant adeno-associated virus vector carrying human endostatin gene and enhanced green fluorescent proteins gene (rAAV2-endostatin-EGFP) was constructed. Endometrium was from 12 patients with leiomyoma undergoing hysterectomy in Second Hospital, Tianjin Medical University between November and December 2008. Endometriosis models of nude mice were established by transplanting human endometrial fragments intooperitoneal surface. After 1 week, those 60 mice were divided into 3 groups: treatment group including 20 mice injected with rAAV2-endostatin-EGFP to ectopic lesion, control group including 20 mice injected with rAAV2-EGFP to ectopic lesion and blank control group including 20 mice injected with phosphate buffered saline (PBS) to the ectopic lesion. At 1, 2 and 3 weeks after treatment, those mice underwent laparotomy to observe the location and size of ectopic lesion in abdominal cavity. The expression of endostain protein, number of gland, microvessel density (MVD) and vascular endothelial growth factor (VEGF) were measured in ectopic lesions. The serum level of estradiol and progesterone were detected in nude mice among every groups. RESULTS: (1) All endometriosis of nude mice models were established successfully through peritoneum transplanting. After 1 week's treatment, flat lesion nodes, decreased gland number and narrow and atrophy glandular cavity were observed by light microscope. (2) The endostatin gene was transferred into nude mice successfully and expressed effectively. It was observed that endostatin protein expression was shown with enhanced green fluorescent proteins in ectopic lesion. (3) Glands number of ectopic lesion in rAAV2-endostatin-EGFP group (7.8 ± 1.9, 7.0 ± 1.5 and 5.5 ± 1.7) were significantly less than 10.1 ± 1.7, 10.2 ± 2.0 and 9.8 ± 2.4 in rAAV2-EGFP control group and 10.2 ± 2.2, 10.0 ± 2.0 and 9.7 ± 2.2 in PBS control group at 1, 2 and 3 weeks after treatment (all P < 0.05). Glands number of ectopic lesion in rAAV2-endostatin-EGFP group at 3 weeks was significantly less than those at 1 and 2 weeks after treatment (P < 0.05). (4) MVD of ectopic lesion in rAAV2-endostatin-EGFP group (12.2 ± 1.5, 11.4 ± 2.1 and 9.0 ± 1.4) was significantly less than those at rAAV2-EGFP control group (16.5 ± 1.7, 16.5 ± 1.9 and 16.9 ± 1.9) and PBS control group (16.2 ± 1.6, 16.0 ± 1.6 and 16.3 ± 1.7) at 1, 2 and 3 weeks after treatment (all P < 0.05). MVD of ectopic lesion in rAAV2-endostatin-EGFP group at 3 weeks was significantly less than those at 1 and 2 weeks after treatment (P < 0.05). (5) The rate and density of VEGF expression at ectopic lesion in rAAV2-endostatin-EGFP group (35%, 30%, 25% and 1.60 ± 0.43, 1.33 ± 0.30, 1.03 ± 0.36) were significantly less than those at rAAV2-EGFP control group (80%, 75%, 85% and 2.43 ± 0.53, 2.43 ± 0.29, 2.66 ± 0.45) and PBS control group (85%, 90%, 90% and 2.36 ± 0.53, 2.64 ± 0.57, 2.53 ± 0.52) at one 1, 2 and 3 weeks after treatment (all P < 0.05). The expression of VEGF at ectopic lesion in rAAV2-endostatin-EGFP group at 3 weeks was significantly less than those at 1 and 2 weeks after treatment (P < 0.05). (6) The level of estradial and progesterone in serum of nude mice of rAAV2-endostatin-EGFP group [E(2): (48 ± 7) pmol/L, P: (61 ± 8) nmol/L] did not reach statistical difference when compared with those at rAAV2-EGFP control group [E(2): (50 ± 9) pmol/L, P: (60 ± 10) nmol/L] and PBS control group [E(2): (48 ± 7) pmol/L, P: (58 ± 10) nmol/L, P > 0.05]. CONCLUSIONS: The recombinant adeno-associated virus carrying human endostatin gene therapy could inhibit angiogenesis at endometriotic lesions and not influence steroid level. The antiangiogenic gene therapy might become a novel option for endometriosis.

SPP1 inhibition improves the cisplatin chemo-sensitivity of cervical cancer cell lines.

PURPOSE: Cisplatin (DDP)-based chemotherapy is a standard strategy for cervical cancer, while chemoresistance remains a huge challenge. In the present study, we aimed to explore the effects of SPP1 on the proliferation and apoptosis rate of the HeLa cervical cancer cell line with cisplatin (DDP) resistance. METHODS: Microarray analysis was employed to select differentially expressed genes in cervical cancer tissues and adjacent tissues. Then, we established a DDP-resistant HeLa cell line (res-HeLa). Western blotting was used to detect SPP1 expression in both tissue and cells. After the transfection with si-SPP1 and pcDNA3.1-SPP1, colony formation and MTT assays were applied to detect cell proliferation changes. Flow cytometry was employed to detect the cell apoptosis rate. Western blotting was performed to verify the activation of PI3K/Akt signal pathway proteins related to DDP resistance. RESULTS: SPP1 was overexpressed in cervical cancer tissues and cell lines. Compared to normal HeLa cells, expression of SPP1 was significantly enhanced in res-HeLa cells. SPP1 knockdown resulted in repressed proliferation and enhanced apoptosis of res-HeLa cells, which could be reversed by SPP1 overexpression in HeLa cells. Additionally, downregulation of SPP1 improved the DDP sensitivity of HeLa by inhibiting the PI3K/Akt signaling pathway. CONCLUSION: SPP1 inhibition could suppress proliferation, induce apoptosis and increase the DDP chemo-sensitivity of HeLa cells.

[Relationship between nucleotide excision repair gene ERCC1 and resistance to cisplatin in ovarian cancer].

OBJECTIVE: To study the relationship between nucleotide excision repair gene ERCC1 and resistance to cisplatin in ovarian cancer. METHODS: The expression of gene ERCC1 in 58 ovarian cancer tissues and 4 cell lines were examined and its relationship with resistance to cisplatin were analyzed, the changes of sensitivity to cisplatin were observed after interference of ERCC1 gene with small interfering RNA (siRNA) in ovarian cancer cell lines. RESULTS: In 58 ovarian cancer tissues, the positive rate of ERCC1 protein in chemoresistant cases (57.89%) was higher than that in chemo-sensitive cases (28.21%, P = 0.029). The mRNA levels of ERCC1 gene in ovarian cancer cell lines ES-2, SKOV3, COC1, COC1/DDP were related to cisplatin IC50 values (r = 0.932, P <0.05). The sensitivity of cell lines ES-2, SKOV3, COC1/DDP cells to cisplatin was increased by 53.88, 5.07, and 3.75 times, respectively, after RNA interfering ERCC1 gene. CONCLUSION: ERCC1 gene is associated with the resistance to cisplatin and the sensitivity to cisplatin can be enhanced by RNA interfering ERCC1 in ovarian cancer.

[Influence of mifepristone on DNA repair genes and cisplatin sensitivity in human ovarian cancer drug-resistance cells].

OBJECTIVE: To study the changes of DNA repair genes and enhanced anti-tumor effect of cisplatin induced by mifepristone in human ovarian cancer drug resistance cells. METHODS: The alterations of cisplatin concentration producing 50% inhibition (IC50 ) in the COC1/DDP cell lines were examined by methyl thiazolyl tetrazolium (MTT) assay. RT-PCR and flow cytometry were used to analyze the changes of the mRNA of ERCC1, BRCA1, hMLH1 genes and cell cycle and apoptosis. Subcutaneous implantation of COC1/DDP was established in nude mice and the enhanced anti-tumor effect of cisplatin by mifepristone was observed in vivo. RESULTS: Cisplatin IC50 values of COC1/DDP cell were decreased from (3.71 +/- 0.38) microg/ml to (3.18 +/- 0.46), (1.95 +/- 0.14), (0.64 +/- 0.18) microg/ml respectively when treated with 2.5, 5.0, 10.0 micromol/L mifepristone. Mifepristone could down-regulate the mRNA levels of ERCC1, BRCA1, hMLH1 genes and enhance G0/G1 phase block effect of cisplatin, and 2.5, 5.0, 10.0 micromol/L mifepristone combined with cisplatin increased rate of cell apoptosis from 0.08% to 5.11%, 9.13% and 12.24% respectively. The percentage of inhibition of xenograft tumor volume in combined treatment group was 70.1%, which was significantly different (P < 0.05). CONCLUSION: By down-regulating ERCC1, BRCA1, hMLH1 genes, blocking G0/G1 phase, and increasing apoptosis rate, mifepristone could enhance anti-tumor effect of cisplatin.

[Enhanced cisplatin cytotoxicity by RNA interfering the excision repair cross-complementing 1 gene in ovarian cancer cell lines].

OBJECTIVE: To study changes of cisplatin sensitivity by RNA interfering the excision repair cross-complementing (ERCC) 1 gene in ovarian cancer cell lines. METHODS: The small interference RNA (siRNA) targeting ERCC1 gene was designed and synthesized by transcription in vitro, and transfected to ovarian cancer cell line ES-2. The mRNA and protein of ERCC1 were evaluated by means of RT-PCR, western blot and immunocytochemistry. The changes of cisplatin sensitivity after interference were examined by methyl thiazolyl tetrazolium (MTT) assay. RESULTS: In ES-2 cell, the mRNA and protein levels of ERCC1 were dramatically decreased 24, 48 and 72 hours after transfection. The sensitivity to cisplatin of ES-2 cell line was increased by 53.88 times after disturbing the ERCC1 gene. CONCLUSION: The sensitivity to cisplatin of ovarian cancer cell lines ES-2 could be enhanced by RNA interfering ERCC1 gene.

Overexpression of long non-coding RNA PVT1 in ovarian cancer cells promotes cisplatin resistance by regulating apoptotic pathways.

Ovarian cancer is the most lethal gynecologic malignancy. Cisplatin is a very effective cancer chemotherapy drug, but cisplatin resistance is a crucial problem of therapy failure. Overexpression of PVT1 has been demonstrated in ovarian cancer. The mRNA level of PVT1 in ovarian cancer tissues of cisplatin-resistant patients and cisplatin-sensitive patients, cisplatin-resistant cells SKOV-3/DDP and A2780/DDP, cisplatin-sensitive cells SKOV-3 and A2780 were determined by qRT-PCR. The influence of the knockdown or overexpression of PVT1 on cisplatin resistance was measured by measuring the cytotoxicity of cisplatin and the apoptotic rate of ovarian cancer cells was detected by CCK-8 assay and flow cytometry, respectively. The mRNA levels and protein expression of TGF-ß1, Smad4, p-Smad4 and Caspase-3 in apoptotic pathways were determined. The mRNA level of PVT1 was significantly higher in ovarian cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. SKOV-3/DDP and A2780/DDP cell viability and the percentage of apoptotic cells after transfection with PVT-1 siRNA and treated with cisplatin was markedly lower and higher than the control, respectively. Moreover, the overexpression of PVT1 exhibited the anti-apoptotic property in SKOV-3 and A2780 cells after transfection with LV-PVT1-GFP and treated with cisplatin. The mRNA levels and protein expression of TGF-ß1, p-Smad4 and Caspase-3 were much higher in cisplatin-resistant cells transfected with siPVT1. Overexpression of LncRNA PVT1 in ovarian cancer promotes cisplatin resistance by regulating apoptotic pathways.

CYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro.

Ovarian cancer (OC) is the most frequent cause of mortality among gynecological malignancies, with a 5-year survival rate of approximately 30%. The standard regimen for OC therapy includes a platinum agent combined with a taxane, to which the patients frequently acquire resistance. Resistance arises from the oxidation of anticancer drugs by CYP1B1, a cytochrome P450 enzyme overexpressed in malignant OC. The aim of the present study was to determine the role of CYP1B1 expression in the drug resistance of OC to the taxane, paclitaxel (PTX). Immunohistochemical staining was used to assess CYP1B1 expression in a panel of ovarian samples (53 primary cancer samples, 14 samples of metastastic cancer, 30 benign tumor samples and 19 normal tissue samples). Semi-quantitative RT-PCR was also performed to determine CYP1B1 expression in several OC cell lines. Finally, we used proliferation and toxicity assays, as well as a mouse xenograft model using nude mice to determine whether α-naphthoflavone (ANF), a CYP1B1 specific inhibitor, reduces resistance to PTX. CYP1B1 was overexpressed in the samples from primary and metastatic loci of epithelial ovarian cancers. In some cell lines, PTX induced CYP1B1 expression, which resulted in drug resistance. Exposure to ANF reduced drug resistance and enhanced the sensitivity of OC cells to PTX in vitro and in vivo. The expression profile of CYP1B1 suggests that it has the potential to be a useful diagnostic marker and prognostic factor for malignant OC. The inhibition of CYP1B1 expression by specific agents may provide a novel therapeutic strategy for the treatment of patients resistant to PTX and may improve the prognosis of these patients.

Neoadjuvant intraarterial chemotherapy and embolization in treatment of advanced ovarian epithelial carcinoma.

BACKGROUND: The purpose of the study was to evaluate the role of neoadjuvant chemotherapy and embolization via the anterior branches of the bilateral internal iliac arteries in treating patients with advanced ovarian epithelial carcinoma. METHODS: Forty-two patients with advanced ovarian epithelial carcinoma (study group) were treated via the anterior branches of the bilateral internal iliac arteries after cytoreductive surgery and 7 courses of adjuvant platinum-based combination chemotherapy. Primary cytoreductive surgery was performed in 43 patients with advanced ovarian epithelial carcinoma (control group), and then followed by 8 courses of adjuvant platinum-based combination chemotherapy. The rate of optimal cytoreductive surgery, survival rate, blood loss during operation and operative time were investigated in the two groups. Statistical significance was assessed using Student's t test, the Chi-square test and the log-rank test. RESULTS: In the study group, the rate of optimum debulking after platinum-based chemotherapy and embolization via the anterior branches of the bilateral internal iliac arteries was 71.43% (30/42) (chi(2) = 10.06, P < 0.005), and 9 (21.43%) of the 42 patients showed no gross residual disease after surgery. Blood loss and operative time were significantly decreased in the study group as compared with those in the control group (665.24 +/- 37.61 ml: 849.31 +/- 41.20 ml, t(1) = 33.21, P(1) < 0.001; 4.23 +/- 0.21 hours: 6.15 +/- 0.38 hours, t(2) = 28.92, P(2) < 0.01). In the study group, the mean survival time and the median overall survival were 33.66 months (95% CI, 24.73 to 42.58) and 26.00 months (95% CI, 19.22 to 32.78), respectively. The median disease-free interval was 18.20 months. In the control group, the mean survival time and the median overall survival were 32.38 months (95% CI, 24.92 to 39.84) and 25.00 months (95% CI, 22.80 to 27.20), respectively. The median disease-free interval was 14.20 months. The overall survival rates were not significantly different between the two groups (chi(2) = 6.48, P > 0.05). CONCLUSIONS: Neoadjuvant platinum-based combination chemotherapy and embolization via the anterior branches of the bilateral internal iliac arteries is an alternative treatment for patients with advanced ovarian epithelial carcinoma, in whom the chance of optimal cytoreductive surgery is low. The treatment can reduce blood loss, decrease operative time, and increase the rate of optimal cytoreductive surgery; but the median survival can't be improved significantly.

[Antisense oligodeoxynucleotides of human telomerse catalytic sub-unit inhibits telomerase activity and proliferation in SKOV3 and COC1].

OBJECTIVE: To study the effects of antisense oligodeoxynucleotides (ODN) of hEST2 (AODN) on telomerase activity and proliferation in ovarian cancer cell lines SKOV3 and COC1. METHODS: Antisense and sense human telomerse catalytic sub-unit (hEST2) phosphorothioate (SODN) and random ODN were designed, synthesized and transfected into SKOV3 and COC1 cells by lipofectamine. The expression of hEST2 mRNA and telomerase activity in SKOV3 and COC1 were tested by reverse transcription-polymerase chain reaction and telomeric repeat amplification protocol before and after transfection. The proliferation and growth in SKOV3 and COC1 were also investigated by methyl thiazolyl tetrazolium and growth curve before and after transfection. RESULTS: AODN could down-regulate the expression of hEST2 mRNA, inhibit telomerase activity and proliferation of ovarian cell lines. The efficiency depends on dose and period of administration. At 48 h, 30 micromol/L AODN had the highest activity. The expression of hEST2 mRNA were declined 54.6% and 44.6% in SKOV3 and COC1 respectively. And also the inhibition of telomerase activity were 47.9% and 42.7% respectively in the two cell lines. CONCLUSIONS: AODN of hEST2 clearly inhibited the proliferation of ovarian cancer cell lines. hEST2 may thus be a new target of gene therapy in ovarian carcinoma.

[In vitro study on hormonal regulation of human endometrial stroma cell decidualization].

OBJECTIVE: To investigate the roles of luteinizing hormone releasing-hormone (LHRH), follicle stimulating hormone (FSH), human chorionic gonadotropin (hCG) and ovary steroids in regulation of human endometrial stroma cell (ESC) decidualization. METHODS: Stroma cells derived from human endometrium during the proliferative phase were cultured in vitro and treated with physiological doses of estradiol (E(2)), testosterone (T), progesterone (P) or LHRH, FSH and hCG. Their morphologic changes and prolactin (PRL) production in the media were examined and compared. RESULTS: Addition of E(2) or T or P stimulated ESC proliferation, resulting in increase of the saturation density. The fibroblast- morphologic changes to polygonal shape and began to express PRL simultaneously after treatment of P or T. P in presence of E(2) or T significantly enhanced PRL production (P < 0.01), suggesting a synergistic action between them in stimulating ESC decidualization. LHRH, FSH or hCG also induced morphologic changes and PRL production by ESC in the presence of E(2) + P. Among them the impact of hCG is most remarkable, especially in this culture system. CONCLUSIONS: E(2), T and P play an important role in proliferation and differentiation of the ESC. LHRH, FSH, hCG also directly exert an effect on ESC decidualization.

[Effect of luteinized granulosa cell conditioned medium on cortical granule of mouse oocytes matured in vitro].

OBJECTIVE: To study the effect of luteinized granulosa cell conditioned medium on cortical granule (CG) of the mouse oocytes matured in vitro. METHODS: Oocytes in germinal vesicle (GV) stage of Kunming mice were randomly divided into 2 groups according to different in vitro maturation (IVM) culture media. The study group medium contained 50% granulosa cell condition medium, follicle stimulating hormone 75 U/L and estrodial 1 nmol/L. The control group medium contained follicle stimulating hormone 75 U/L and estrodial 1 nmol/L. Oocytes were cultured for 16 or 18 hours. CG was examined by fluorescein isothiocyanate labeled Lens culinaris agglutinin under a confocal scanning laser microscope. RESULTS: After cultured for 16 hours, the nuclear maturation rates of control and study groups were 70.0% and 76.5%. After cultured for 18 hours, the maturation rates were 75.1% and 83.1%, respectively. There was no significant difference between the two groups. After cultured for 16 hours, there was no pronuclear formation in both groups. When culture was extended to 18 hours, fertilization occurred. After cultured for 16 hours, the rates of CGs forming a line under membrane were 10.0% and 50.0% in control and study groups respectively. When culture was extended to 18 hours, the rates rose to 57.1% and 91.6% accordingly. The rate of 18 h of each group was significantly higher than that of 16 h (both P < 0.001). The rate of study group of 18 h was significantly higher than that of control group (P < 0.05). CONCLUSION: Granulosa cell conditioned medium could improve the mouse oocytes maturation competence in vitro.

MDM2 sensitizes a human ovarian cancer cell line.

OBJECTIVES: The purpose of this study was to determine whether overexpression of MDM2 could sensitize the ovarian cancer cell line A2780. METHODS: The wild-type p53-expressing cell line A2780 was stably transfected with pCMV-MDM2 (A2780-MDM2) or pCMV (A2780-V) as control. MTT assay and clonogenic survival assay were used to measure the cisplatin sensitivity. FACS and host cell (CAT) reactivation assay were used to estimate the change of cell cycle and ability of repairing cisplatin-induced DNA damage. RESULTS: Parental A2780 and A2780-V had similar cisplatin sensitivities, whereas A2780-MDM2 was two- to threefold more sensitive to cisplatin. Repair of cisplatin-induced DNA damage was reduced in A2780 cells overexpressing MDM2, compared to A2780 cells in which wild-type p53 function was intact. After cisplatin treatment, A2780-MDM2 cells showed a pronounced S-phase arrest; however, A2780 cells with intact wild-type p53 arrested primarily in G2/M phase. CONCLUSIONS: MDM2 overexpression can increase cisplatin cytotoxicity in A2780, with loss of G1/S checkpoint control and decreased cisplatin-DNA adduct repair. This suggests that ovarian cancers that overexpress MDM2 may be amenable to treatment with platinum compounds.