Preclinical assessment of the VEGFR inhibitor axitinib as a therapeutic agent for epithelial ovarian cancer.

Axitinib, small molecule tyrosine kinase inhibitor, demonstrates anti-cancer activity for various solid tumors. We investigated anti-cancer effect of axitinib in epithelial ovarian cancer (EOC). We treated EOC cells (A2780, HeyA8, RMG1, and HeyA8-MDR) with axitinib to evaluate its effects on cell viabilty, apoptosis and migration. Western blots were performed to assess VEGFR2, ERK, and AKT levels, and ELISA and FACS to evaluate apoptosis according to axitinib treatment. In addition, in vivo experiments in xenografts using A2780, RMG1, and HeyA8-MDR cell lines were performed. We repeated the experiment with patient-derived xenograft models (PDX) of EOC. Axitinib significantly inhibited cell survival and migration, and increased apoptosis in EOC cells. The expression of VEGFR2 and phosphorylation of AKT and ERK in A2780, RMG1, and HeyA8 were decreased with axitinib treatment in dose-dependent manner, but not in HeyA8-MDR. In in vivo experiments, axitinib significantly decreased tumor weight in xenograft models of drug-sensitive (A2780), and clear cell carcinoma (RMG1) and PDX models for platinum sensitive EOC compared to control, but was not effective in drug-resistant cell line (HeyA8-MDR) or heavily pretreated refractory PDX model. Axitinib showed significant anti-cancer effects in drug-sensitive or clear cell EOC cells via inhibition of VEGFR signals associated with cell proliferation, apoptosis and migration, but not in drug-resistant cells.

Value of sonohysterography in preoperative assessment of myometrial invasion for patients with endometrial cancer.

OBJECTIVE: The aims of this study were to compare the diagnostic performance of sonohysterography (SH) with that of magnetic resonance imaging (MRI) in estimation of myometrial invasion and to evaluate the influence of SH on peritoneal cytologic results for patients with endometrial cancer. METHODS: Seventy-four patients with endometrial cancer were included. Sonohysterography and MRI were performed before surgery. All patients had complete staging procedures, including peritoneal cytologic analyses. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for SH and MRI. RESULTS: The concordance rates of myometrial invasion for SH and MRI were 82.4% and 81.1%, respectively. The sensitivity, specificity, PPV, and NPV for identification of deep myometrial invasion were 64.7%, 87.7%, 61.1%, and 89.3% on SH and 70.6%, 84.2%, 57.1%, and 90.6% on MRI. Two patients (2.7%) were found to have positive results for malignant cells on peritoneal cytologic analyses. CONCLUSIONS: Sonohysterography appears to be a useful preoperative method for predicting myometrial invasion, comparable to MRI.

Duplex pyrosequencing of the TPMT*3C and TPMT*6 alleles in Korean and Vietnamese populations.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) genetic polymorphisms have been studied intensively in relation to thiopurine toxicity. In the present study, an improved pyrosequencing method was developed for TPMT genotyping and used to investigate the genotype frequency in Korean and Vietnamese populations. METHODS: Four-hundred Korean and 159 Vietnamese subjects were genotyped by pyrosequencing for TPMT 238G>C, 460G>A, 539A>T, and 719A>G variants, in order to determine the TPMT*2, *3A, *3B, *3C, and *6 alleles. RESULTS: TPMT*3C was found to be the most frequent allele in both the Korean (0.88%) and Vietnamese (2.83%) populations. TPMT*2, *3A, and *3B were not found in either of the study populations. Two Korean subjects were genotyped as TPMT*1/*6 (0.25%), while none of the Vietnamese had this genotype. The direct comparison of the frequencies of functional TPMT1/3C genotype showed significant difference between Korean and Vietnamese populations (chi2 test, p=0.0124). Duplex pyrosequencing methods for the detection of TPMT3C and TPMT6 were developed and validated to show 100% concordance with the results obtained by direct sequencing. CONCLUSIONS: The functional TPMT alleles in Korean and Vietnamese populations are TPMT*3C and TPMT*6. Duplex pyrosequencing for these alleles appears to be an accurate, rapid, and cost-effective method for genotyping TPMT in these Asian populations.