Mutation Profiles of Ovarian Seromucinous Borderline Tumors in Japanese Patients.

Ovarian seromucinous tumors (SMBTs) are relatively rare, and their carcinogenesis is largely unknown. In this study, the molecular features of SMBTs in Japan are assessed. DNA was extracted from microdissected paraffin-embedded sections from 23 SMBT cases. Genetic mutations (KRAS, BRAF, PIK3CA, and ERBB2) were evaluated using Sanger sequencing. Immunohistochemistry for p53, ARID1A, and PTEN was also performed as a surrogate for the loss of functional mutations in these tumor suppressor genes. The prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations was 4.3% (1/23), 8.6% (2/23), 8.6% (2/23), and 17.3% (4/23), respectively. Overexpression or loss of p53 expression occurred in 26% (6/23), loss of ARID1A expression in 4.3% (1/23), and none of the cases showed expression of PTEN loss. These findings suggest that KRAS/BRAF/PIK3CA and PTEN mutations are rare carcinogenic events in SMBTs. The high frequency of positive p53 staining and a low frequency of loss of ARID1A staining suggests that SMBT carcinogenesis may be related to the alteration of p53 rather than that of ARID1A. ERBB2 oncogenic mutations may play an important role in the tumorigenesis of Japanese SMBTs.

Uterine lipoleiomyoma in an elderly patient: a case report.

BACKGROUND: Uterine lipoleiomyoma is a rare, fat-containing, benign tumor. The clinical features and optimal treatment of this tumor remain unclear. CASE: An 80-year-old woman with an extensive cardiac history was referred for assessment of a huge pelvic mass. Magnetic resonance imaging demonstrated a uterine tumor with inhomogeneously high signal intensity. A fat suppression technique showed heterogeneous suppression of the signal intensity, with areas of increased enhancement after Gd-DTPA administration. Hysteroscopy revealed no abnormal findings in the endometrium. She underwent a simple total abdominal hysterectomy, with a preoperative diagnosis of uterine liposarcoma. Histological examination revealed a uterine lipoleiomyoma. Ten days after surgery, she died due to acute non-occlusive mesenteric ischemia. CONCLUSION: In cases where the radiological appearance of a uterine tumor in an elderly patient is suspicious for liposarcoma, the possibility of a benign lipoleiomyoma should be considered. Careful consideration of the patient's preoperative condition and familiarity with uterine fat-containing tumors are essential for determining an optimal therapeutic approach.

Successful continuation of pregnancy after repair of a midgestational uterine rupture with the use of a fibrin-coated collagen fleece (TachoComb) in a primigravid woman with no known risk factors.

We report the first case of successful continuation of pregnancy after repair of a midgestational uterine rupture with the use of a fibrin-coated collagen fleece (TachoComb, Nycomed, Linz, Austria). For midgestational uterine rupture, adequate uterine repair and close surveillance of preterm labor could improve perinatal outcome by permitting continuation of the pregnancy.

Endometrial carcinosarcoma presenting as a tibial metastasis.

Metastasis to a lower-extremity bone is an extremely rare event in patients with endometrial carcinoma. A 64-year-old woman presented with progressive right leg pain but no gynecologic complaints. A diagnostic workup revealed primary endometrial carcinosarcoma with an isolated tibial metastasis. Though the patient received only local irradiation to the tibial lesion, complete resolution of symptoms resulted. Six months after the radiotherapy, the intraabdominal disease progressed and the patient died. We note that tibial metastasis is one of the possible presenting symptoms in patients with endometrial malignant tumors. Irradiation can improve their quality of life and so may be effective in the management of symptomatic tibial metastasis.

Spontaneous regression in recurrent epithelial ovarian cancer.

BACKGROUND: Although spontaneous regression has been reported in several cancers, it is generally believed that this rare phenomenon does not occur in epithelial ovarian cancer. CASE: We presented a stage IV epithelial ovarian cancer patient with long-term disease-free survival after palliative local irradiation alone against recurrence. The recurrent supraclavicular lymph node was almost completely necrotic, and the swelling of the para-aortic lymph node spontaneously regressed. CONCLUSION: The histologic features and unexpected clinical course in this patient strongly suggest that spontaneous regression occurred in recurrent epithelial ovarian cancer.

Adenocarcinoma in situ coexisting with carcinoma in situ of the cervix during pregnancy.

CASE REPORT: We report a pregnant patient with adenocarcinoma in situ (AIS) coexisting with carcinoma in situ (CIS) of the cervix diagnosed by conization at 16 weeks' gestation. Apoptotic activity was higher in the CIS lesion than in the AIS lesion in the cone biopsy specimen. Postpartum evaluation confirmed the disappearance of CIS lesion with positive cone margins, however, multifocal AIS with negative cone margins was found. CONCLUSION: Clinical course and biological features of AIS associated with pregnancy may be different from those of CIS.

Expression of the angopoietin-1, angopoietin-2, Tie2, and vascular endothelial growth factor gene in epithelial ovarian cancer.

OBJECTIVES: Angiopoietin/Tie2 system with vascular endothelial growth factor (VEFG) is known to be important for the initiation of angiogenesis in tumors. The aim was to evaluate whether angiopoietin/Tie2 system with VEFG affects prognosis in patients of epithelial ovarian cancer. METHODS: Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie2, and VEGF gene expression were analyzed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 85 epithelial ovarian cancer surgical specimens. These gene expressions were correlated with clinical-pathological parameters, microvessel density (MVD), and patients' survival. RESULTS: Ang-1/Ang-2 gene expression ratio, VEGF, and Tie2 gene expression significantly associated with MVD, respectively (P < 0.0001, P = 0.024, P = 0.005). The patients with low Ang-1/Ang-2 gene expression ratio and high VEGF gene expression were found to have a significantly higher MVD when compared to others (P = 0.0003). Moreover, there was a significant difference between the values of MVD in patients with low Ang-1/Ang-2 gene expression ratio and high VEGF and high Tie2 gene expression and those in others (P = 0.0025). FIGO stage (P = 0.014), residual disease (P = 0.042), histological grade (P = 0.028), Ang-1/Ang-2 gene expression ratio (P = 0.010), and combination of Ang-1/Ang-2 gene expression ratio and VEGF gene expression (P = 0.019), were found to be significantly associated with a poor prognosis in univariate Cox regression analysis. Multivariate Cox regression analysis revealed that FIGO stage is an independent prognostic factor (P = 0.035). Low Ang-1/Ang-2 gene expression ratio had a tendency to be an independent prognostic factor (P = 0.061). CONCLUSIONS: Angiogenesis occurred by angiopoietin/Tie2 system in concert with VEGF in epithelial ovarian cancer did not affect patients' survival. However, gene expression of Ang-1 and Ang-2 might present a pertinent diagnostic tool to select a high-risk group of patients independent of clinical-pathological parameters and a new insight to understand the biology of epithelial ovarian cancer.

Evaluation of the antiangiogenic effect of Taxol in a human epithelial ovarian carcinoma cell line.

PURPOSE: Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are major ligands for the endothelium-specific tyrosine kinase receptor Tie-2 and are important regulators of endothelial cell survival. In the presence of vascular endothelial growth factor (VEGF), vessel destabilization by Ang-2 has been hypothesized to induce an angiogenic response, but in the absence of VEGF, Ang-2 leads to vessel regression. In the present study, a human ovarian cancer cell line was used to investigate the possibility that Taxol might affect the expression of Ang-1, Ang-2, and VEGF. MATERIALS AND METHODS: KF 28, a single-cell clone of a human ovarian epithelial carcinoma cell line, was used. The expression of Ang-1, Ang-2, and VEGF was assessed by quantitative real-time RT-PCR and Western blot analysis or enzyme-linked immunosorbent assay. Conditioned medium was used in the in vitro angiogenesis assay. RESULTS: The concentration of Taxol that inhibited the growth of cells to the level of 50% of control cell growth was 4.65+/-0.35 nM. Quantitative real-time RT-PCR indicated that Ang-1 gene expression was significantly decreased by exposure to 2 nM Taxol for 168 h ( P<0.05 vs control cells). Western blot analysis confirmed that the Ang-1 protein level was decreased by exposure to 2 nM Taxol for 168 h. Ang-2 gene expression did not significantly differ between control cells and those exposed to Taxol for any of the indicated times. The Ang-1/ Ang-2 gene expression ratio was significantly decreased by exposure to Taxol for 168 h ( P<0.05 vs control cells). VEGF gene expression was significantly decreased by exposure to Taxol for 168 h ( P<0.05). The VEGF concentration in the conditioned medium was also significantly reduced by exposure to Taxol for 168 h ( P<0.05). Conditioned medium collected following Taxol treatment for 168 h significantly inhibited endothelial tubule formation ( P<0.05). Cell growth did not significantly differ between control cells and those exposed to Taxol for any of the indicated times. CONCLUSIONS: Our results show that exposure of ovarian cancer cells to a low concentration of Taxol may inhibit the initiating event in angiogenesis, namely, vascular regression. This information might be valuable in the development of new therapeutic interventions for epithelial ovarian cancer.

Dihydropyrimidine dehydrogenase in normal and malignant endometrium: relationship with cell proliferation and thymidine phosphorylase.

Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine salvage enzyme responsible for degradation of thymine, which is produced from thymidine by thymidine phosphorylase (TP). Our purpose was to determine the relationship between DPD, cell proliferation and TP expression in human endometrium. We examined DPD gene expression using reverse transcription-polymerase chain reaction, DPD protein levels using enzyme-linked immunosorbent assay, and DPD protein localization using immunohistochemistry in 58 normal endometria and 28 endometrial cancers. DPD gene expression was then related to the proliferating cell nuclear antigen index and to TP gene expression. DPD gene expression, which was correlated with DPD protein level, was relatively stable throughout various menstrual phases but was significantly elevated in postmenopausal status. It was significantly lower in endometrial cancer than in normal endometrium. Localization analysis revealed that DPD protein was located primarily in epithelial cells, but was also present in stromal cells. DPD gene expression correlated inversely with the PCNA index. TP gene expression pattern contrasted with that of DPD in postmenopausal and malignant endometrium. A high ratio of TP to DPD gene expression was significantly more frequent in endometrial cancer than in normal endometrium in any menstrual phase. DPD may act cooperatively with TP to affect cell function by maintaining the pyrimidine nucleotide pool balance in normal and malignant endometrium.

Induction of thymidine phosphorylase expression and enhancement of Furtulon sensitivity by Taxol in a human ovarian carcinoma cell line.

OBJECTIVE: Thymidine phosphorylase (TP) is one of the enzymes involved in the salvage pathways of nucleotide synthesis. The enzyme converts thymidine to thymine and 2'-deoxyribose-1-phosphate and can also metabolize the prodrug 5'-deoxy-5-fluorouridine (Furtulon) to 5-fluorouracil and 5'-deoxy-D-ribose-1-phosphate. The aim of this study was to determine whether Paclitaxel (Taxol) induces TP expression and whether increased TP expression is further sensitized to Furtulon, using a human ovarian carcinoma cell line. MATERIAL AND METHODS: KF 28, a single-cell clone of a human ovarian carcinoma cell line, was used. TP expression was assessed by RT-PCR and Western blot analysis. Cell growth was evaluated by MTT assay. RESULTS: The concentration of Taxol that inhibited the growth of cells to the level of 50% of the control growth was 4.65 +/- 0.35 nM. TP gene expression was significantly increased at 72 hours 1 nM Taxol exposure compared to the control by RT-PCR (p = 0.020). Western blot analysis confirmed that the TP protein level was elevated compared to the control at 72 hours 1 nM Taxol exposure. Cell growth did not significantly differ between the control and 72 hours 1 nM Taxol exposure groups (p = 0.917). After 48 hours treatment with Furtulon followed by 72 hours 1 nM Taxol exposure, cell growth was dose-dependently inhibited in Taxol-treated cells (p = 0.022), but not in non-Taxol-treated cells (p = 0.082). CONCLUSION: Our results show that a low concentration of Taxol is a candidate for increasing TP expression in a human ovarian carcinoma cell line, and that cells with an elevated level of TP expression can be further sensitized to Furtulon. This information might be valuable in the development of new therapeutic interventions for epithelial ovarian cancer.

Induction of thymidine phosphorylase expression by Taxol does not enhance Furtulon sensitivity in a cisplatin-resistant human ovarian carcinoma cell line.

OBJECTIVE: Thymidine phosphorylase (TP) can metabolize the prodrug 5'-deoxy-5-fluorouridine (Furtulon) to 5-fluorouracil (5-FU) and 5'-deoxy-D-ribose-1-phosphate. Furthermore, TP may enhance the toxicity of the active drug 5-FU by the transfer of 2'-deoxyribose 1-phosphate, so producing 5-fluoro-2'-deoxyuridine. This product can form 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) through the action of thymidine kinase, and FdUMP in turn can inhibit thymidylate synthase (TS), leading to reduced thymidylate formation and subsequent inhibition of DNA synthesis. The aim of this study was to determine whether the expression of TP is associated with the sensitivity to Furtulon, using a single-cell clone of the human ovarian carcinoma cell line, KF-28, and KFr13, a cisplatin-resistant subline derived from KF28 cells. Next, if lower TP expression correlated with decreased sensitivity to Furtulon, we planned to investigate the possibility that increased TP expression induced by Paclitaxel (Taxol) exposure might increase the sensitivity to Furtulon. MATERIALS AND METHODS: Cell growth was evaluated by MTT assay. TP and TS expression were assessed by RT-PCR and Western blot analysis. RESULTS: Cell growth was significantly inhibited compared to the control at 10 (p < 0.0001), 100 (p < 0.0001) and 1000 microM (p < 0.0001) of Furtulon after 24 hours Furtulon treatment in KF28. However, cell growth was significantly inhibited only at 1000 microM (p < 0.0001), in KFr13. The expression of TP was observed only in KF28 in our PCR condition. Next, Western blot analysis confirmed that TP protein levels in KF28 were markedly elevated compared to those in KFr13. TP gene expression emerged at 72, 96 and 120 hours after 0.5 nM Taxol (about twenty percent of IC50; 2.61 +/- 0.06 nM) exposure to KFr13 in our PCR condition. The level of TP gene expression was the highest at 120 hours Taxol exposure. Similarly, Western blot analysis showed that the TP protein level of KFr13 cells 120 hours after Taxol exposure (KFr13/120 hours Taxol exposure) was elevated compared to the control. Cell growth did not significantly differ between KFr13 and KFr13/120 hours Taxol exposure cells. KFr13 and KFr13/120 hours Taxol exposure cells were incubated with 0-1000 microM Furtulon for 24 hours-168 hours. Furtulon sensitivity of KFr13/120 hours Taxol exposure cells was not found to be significantly enhanced compared to that of KFr13 cells at any of the indicated times. The level of TS gene expression assessed by RT-PCR in KFr13 and KFr13/120 hours Taxol exposure cells was significantly lower than that in KF28 cells (p < 0.001). Moreover, higher protein level expression of TS was noted in KF28 cells compared to KFr13 or KFr13/120 hours Taxol exposure cells. CONCLUSION: Our results suggest that lower expression of TP is not a critical determinant in the development of resistance to Furtulon in the cisplatin-resistant human ovarian carcinoma cell line, KFr13. The clinical relevance of these observation remains to be established.

Prognostic value of overexpression of p53 in human ovarian carcinoma patients receiving cisplatin.

A major obstacle to the treatment of ovarian carcinoma is intrinsic/acquired resistance to cisplatin-based chemotherapy. The clinical significance of p53 overexpression in patients with ovarian carcinoma is still controversial. The aim of this study was to investigate the independent prognostic significance of p53 overexpression in patients with ovarian carcinoma who are treated with cisplatin. We retrospectively examined the overexpression of p53 in primary ovarian carcinoma, and its association with chemotherapeutic efficacy. One hundred and thirty four ovarian carcinomas were surgically removed from patients who received adjuvant cisplatin-based chemotherapy. Immunohistochemical analysis of p53 was performed using a DO7 antibody against the p53 protein in 134 ovarian carcinomas. The significance of p53 in the prognosis of patients with ovarian carcinomas was also examined by a survival analysis of mortality follow-up data covering the period from 1988 to 2001. Thirty-three tumors (25%) exhibited p53 overexpression. Overexpression of p53 in grade 2/grade 3 tumors was significantly higher than that seen in grade 1 tumors (P=0.0088, 0.0229). Patients with tumors who also showed overexpression of p53 had a significantly inferior response to chemotherapy compared with the patients with p53-negative tumors (P=0.04). Cox regression analysis revealed that p53 overexpression was prognostic for poor disease outcome after adjustment for FIGO stage, grade and residual tumor. These findings suggest that overexpression of p53 in ovarian carcinoma is associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, detection of p53 overexpression using the DO7 antibody may be considered as a predictive marker of chemoresistance for cisplatin in patients with ovarian carcinoma.

Allelotypes as potential prognostic markers in ovarian carcinoma treated with cisplatin-based chemotherapy.

We analyzed a series of ovarian carcinomas from patients treated with cisplatin-based chemotherapy for loss of heterozygosity (LOH) to determine the relationship between microsatellite alteration and prognosis. Patients with tumors that had lost alleles at loci 3p14-21, 12qter, or 17p13.3 showed significantly reduced survival compared to patients with tumors that retained both alleles at those loci. The 5-year mortality rates for patients exhibiting allele loss and patients with allele retention were 50 and 41%, respectively, for the 3p14-21 locus (P=0.0023); 57 and 24%, respectively, for 12qter (P=0.0256); and 55 and 40%, respectively, for 17p13.3 (P=0.0489). A statistically significant difference was also observed with respect to fractional allelic loss (FAL), which was a significant indicator for disease recurrence (P=0.0227). The prognosis of patients with high FAL values were significantly worse compared to those with low FAL values (P=0.0306). Our results suggested that LOH at loci 3p14-21, 12qter, or 17p13.3 was a significant predictor of poor survival in ovarian carcinomas treated with cisplatin-based chemotherapy. Furthermore, the association of FAL value with therapy response indicated that ovarian carcinomas with high levels of chromosomal alteration may be more resistant to this type of chemotherapy.

Clinical significance of interleukin-1 receptor antagonist in patients with cervical carcinoma.

OBJECTIVE: Our purpose was to determine the clinical significance of interleukin-1 receptor antagonist (IL-1ra), which is an endogenous inhibitor cytokine of IL-1, in patients with cervical carcinoma. METHODS: Tissue IL-1ra expression and serum IL-1ra level were examined by enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemistry in normal controls and patients with cervical carcinoma. RESULTS: Tissue IL-1ra protein level by ELISA was significantly higher in squamous cell carcinoma (n = 9) than in the normal cervix (n = 7) and adenocarcinoma (n = 3). Western blotting confirmed the main presence of intracellular IL-1ra type 1 in squamous cell carcinoma. Immunohistochemistry demonstrated significant IL-1ra expression only in tumor cells of squamous cell carcinoma. Elevation of serum IL-1ra level was found in patients with squamous cell carcinoma (n = 38) compared to normal women (n = 13), but not in patients with adenocarcinoma (n = 9). Although serum IL-1ra level did not correlate with clinical stage or any other tumor marker, high serum IL-1ra level was associated with pelvic lymph node metastasis and poor prognosis in patients with squamous cell carcinoma. On the other hand, these results were not obtained in patients with cervical adenocarcinoma. CONCLUSION: IL-1ra may play important roles in local and general malignant behaviors in patients with cervical squamous cell carcinoma, and measurement of serum IL-1ra level may be useful in predicting patient survival.

The proliferative activity of ovarian tumors of low malignant potential differs from that of ovarian carcinoma.

Ovarian tumors of low malignant potential (LMPs) are intermediate between adenomas and ovarian carcinomas (OCs); however, whether an LMP is a precursor of OC or is a unique type of tumor that will not progress to OC is still controversial. To gain better insight into the relationship between LMP and OC, we compared proliferative and apoptotic activity and tumor size in 50 cases of LMP and 27 cases of OC. We employed immunohistochemical staining with Ki-67 and apoptotic labeling was based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. The average tumor size observed in mucinous LMP was significantly larger than that in mucinous OC (p = 0.014). In contrast, there was no difference in tumor size between serous OC and serous LMP. The average Ki-67 labeling index (LI) in mucinous OC was significantly higher than that in mucinous LMP (p = 0.028). There was no difference between serous OC and serous LMP in the Ki-67 LI. There was also no difference in apoptotic indeed (AI) between OC and LMP, irrespective of histological subtype. A significant positive relationship between the Ki-67 LI and tumor size was observed in mucinous LMP (R = 0.516, p = 0.0003). Interestingly, the Ki-67 LI was inversely correlated with tumor size in mucinous OC (R = 0.570, p = 0.0317). Significant positive correlations between Ki-67 LI and tumor size were observed in both serous LMP and serous OC (R = 0.707, p = 0.0488, R = 0.789, p = 0.0168, respectively). No association was seen between AI and tumor size in LMP and OC, irrespective of histological subtype. The different associations between proliferative activity and tumor size in the mucinous subtype of LMP and OC suggest that mucinous LMPs may not be precursors of mucinous OCs. In contrast, the similar associations of proliferative activity with tumor size in the serous subtype of LMP and OC suggest that serous LMPs may be precursors of serous OCs.

Expression of angiopoietin-1, angiopoietin-2, and Tie2 genes in normal ovary with corpus luteum and in ovarian cancer.

OBJECTIVE: The recent discovery of angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) has provided novel and important insights into the molecular mechanisms of blood vessel formation. Ang1 and Ang2 bind with similar affinity to the endothelial cell tyrosine kinase receptor Tie2. Our purpose was to assess the potential role of the Ang/Tie2 system in physiological and pathological angiogenesis in the ovary. METHODS: Ang1, Ang2, and Tie2 gene expression in 14 normal ovaries with corpus luteum (CL) and in 19 cases of ovarian cancer were analyzed by polymerase chain reaction of RNA after reverse transcription. The level of each gene expression was presented by the relative yield of each gene to the beta(2)-microglobulin gene, respectively. Furthermore, cellular distribution of Ang1 and Ang2 mRNA was examined by in situ hybridization, and localization of Tie2 was studied by immunochemistry. RESULTS: The Ang1, Ang2, and Tie2 gene expression in normal ovary with CL ranged from 0.18 to 1.06 (median 0.54), 0.31-2.64 (median 1.01), and 0.10-0.47 (median 0.20), respectively. The expression of these same genes in ovarian cancer ranged from 0.06 to 0.75 (median 0.14), 0.69-1.59 (median 1.12), and 0.04-0.35 (median 0.15), respectively. Ang1 gene expression in normal ovary with CL was significantly higher than that in ovarian cancer (p = 0.0004). The gene expression levels of Ang2 and Tie2 were statistically the same in both groups. There was a significant correlation between Ang1 gene expression and Tie2 gene expression in normal ovary with CL (r = 0.619, p = 0.018). No such significant correlation was found in ovarian cancer. Moreover, Ang2 gene expression showed no significant correlation with the Tie2 gene expression either in normal ovary with CL or in ovarian cancer. Transcripts for Ang1 were observed in CL cells and endothelial cells around CL, and in tumor cells and endothelial cells at the periphery of tumor invasion. Ang2 transcripts were expressed in the same patterns. Tie2 expression was positive primarily in the endothelial cells around CL and in those at the periphery of tumor invasion. CONCLUSION: Our results indicate that there is a difference in the Ang/Tie2 gene expression between physiological and pathological angiogenesis in the ovary. This finding may aid in the development of new therapeutic interventions for ovarian cancer.

Thymidine kinase in epithelial ovarian cancer: relationship with the other pyrimidine pathway enzymes.

TK is a pyrimidine metabolic pathway enzyme involved in salvage DNA synthesis. What roles TK may play in epithelial ovarian cancer and the relationships between TK and the other pyrimidine pathway enzymes remain unclear. We examined TK1 gene expression by RT-PCR and related it to gene expression of TS, TP and DPD in 69 samples from epithelial ovarian cancer, 8 low-malignant-potential tumors, 16 benign ovarian tumors and 34 normal ovaries. Additionally, cytosolic and serum TK activities were determined by radioenzymatic assay. TK1 gene expression, the ratio of TK1 to TS gene expression, that of TK1 to TP and that of TK1 to DPD were significantly higher in epithelial ovarian cancer than in normal ovaries. In epithelial ovarian cancer, TK1 gene expression correlated with cytosolic and serum TK activities, TS and TP gene expression and the ratio of TP to DPD gene expression. Patients with high-TK1 gene expression had a significantly poorer survival than those with low TK1 gene expression. Combined analysis demonstrated that the relative risk of cancer death for tumors with high TK1, high TS and high TP gene expression was greater than that for tumors with high TK1 gene expression alone. TK1 gene expression together with TS, TP and DPD gene expression may play important roles in influencing the malignant behavior of epithelial ovarian cancer. Combination therapy including TK inhibitor is a possible therapeutic intervention in patients with epithelial ovarian cancer.

Cyclooxygenase-2 expression in endometrial cancer: correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase.

Cyclooxygenase-2 (COX-2), known to be elevated in several human cancers, regulates angiogenesis by inducing production of angiogenic factors. These mechanisms require clarification in endometrial cancer. COX-2 expression was examined by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR) in endometrial cancer, endometrial hyperplasia, and normal endometrium in various phases. We investigated the relationship between COX-2 expression and clinicopathologic variables, microvessel count, and expression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). Immunohistochemistry demonstrated COX-2 protein in cancerous epithelial cells but not in stromal cells. COX-2 expression in epithelial cells was significantly greater in endometrial cancer (n = 63) and endometrial hyperplasia (n = 6) than in normal endometrium in any phase (n = 53). Although COX-2 did not correlate with any conventional clinicopathologic factor in patients with endometrial cancer, COX-2 expression was associated with high microvessel count, VEGF expression, and TP expression. By combined analysis of COX-2, VEGF, and TP, tumors with high expression of at least one factor had a significantly higher microvessel count than tumors expressing little of the three factors. We confirmed upregulation of COX-2 mRNA expression by RT-PCR in endometrial cancer (n = 17) compared to normal endometrium (n = 12). COX-2 mRNA expression significantly correlated with VEGF mRNA expression in these tumors. COX-2 is upregulated in endometrial cancer and facilitates tumor growth via angiogenesis produced in associated with VEGF and TP. Specific inhibition of COX-2 may be a useful therapeutic intervention in endometrial cancer.