Dynamic contrast enhanced­magnetic resonance imaging for the early evaluation of the response to docetaxel in rats with epithelial ovarian cancer.

Dynamic contrast enhanced­magnetic resonance imaging (DCE­MRI) contributes to the early detection and prediction of responses to chemotherapy in cancer. The aim of the present study was to investigate the feasibility of quantitative DCE­MRI parameters for noninvasively predicting the early response to DTX in epithelial ovarian cancer (EOC). In the present study, using 7,12­dimethylbenz (A) anthracene, orthotopic EOC was induced in Sprague Dawley rats. Rats with EOC were treated with docetaxel (DTX) on day 0. DCE­MRI was applied on days 0, 3, 7, 14 and 21. On day 21, the treated tumor types were categorized into sensitive and insensitive groups according to their change in size. Quantitative DCE­MRI parameters were used to assess the early response to therapy. The experiment was performed again, the treatment group was divided into sensitive and insensitive groups according to their initially obtained cut-off values, and histopathological analyses were performed. Comparing the sensitive group with the insensitive group, there were significant differences in the percentage change in the volume transfer constant (Ktrans), rate constant (kep) and initial area under the curve (IAUC) from day 3 and tumor size from day 14. During the early stages of treatment (on day 3), the percentage change of Ktrans combined with kep produced an AUC of 1, and a sensitivity and specificity of 100 and 100%, respectively, using a cut-off value of a 17.59% reduction in Ktrans and kep. From day 7, there were significant differences in the quantitative index percentage change in angiogenesis in the sensitive group compared with the insensitive group. The percentage change in Ktrans, kep and IAUC were positively correlated with the percentage of change in tumor size and angiogenesis, and negatively correlated with the percentage of change in necrosis. The results of the present study indicated that quantitative DCE­MRI parameters were superior to imaging tumor size for the early detection and prediction of the response to DTX chemotherapy in EOC.

Diffusion-weighted imaging and diffusion kurtosis imaging for early evaluation of the response to docetaxel in rat epithelial ovarian cancer.

BACKGROUND: To investigate diffusion-weighted magnetic imaging (DWI) and diffusion kurtosis magnetic imaging (DKI) for the early detection of the response to docetaxel (DTX) chemotherapy in rat epithelial ovarian cancer (EOC). METHODS: 7,12-Dimethylbenz[A]anthracene was applied to induce orthotopic EOC in Sprague-Dawley rats. Rats with EOC were treated with DTX on day 0 (treatment group) or were left untreated (control group). DWI and DKI were performed on days 0, 3, 7, 14 and 21 after treatment. On day 21, the tumors were categorized into the sensitive and insensitive groups according to the size change. The cutoff values of the DWI and DKI parameters for the early response were determined. The experiment was repeated, and the treatment group was divided into the sensitive and insensitive groups according to the initially obtained cutoff values. The DWI and DKI parameters were correlated with tumor size, proliferation, apoptosis and tumor necrosis. RESULTS: In the sensitive vs. insensitive or control group, significant differences were found in the Δ% of the DWI and DKI parameters (ADC, D and K) from day 3 and in tumor size from day 14. Early on day 7, the Δ% of K had an AUC of 1 and sensitivity and specificity values of 100% and 100%, respectively, to detect the response to DTX using a cutoff value of 19.03% reduction in K. From day 7, significant differences were found in the Δ% of Ki-67 and CA125 in the sensitive vs. control group and from day 14 in the sensitive vs. insensitive group. From day 14, there were significant differences in the Δ% of Bcl-2, apoptosis and tumor necrosis in the sensitive vs. control or insensitive group. The Δ% values of ADC and D were negatively correlated with the Δ% values of tumor size, Ki-67, CA125 and Bcl-2 and were positively correlated with the Δ% values of apoptosis and tumor necrosis. The Δ% of K was positively correlated with the Δ% values of tumor size, Ki-67, CA125 and Bcl-2 and was negatively correlated with the Δ% values of apoptosis and tumor necrosis. CONCLUSIONS: DWI and DKI parameters, especially K, are superior for imaging tumor size for the early detection of the response to DTX chemotherapy in induced rat EOC.

The value of DCE-MRI in assessing histopathological and molecular biological features in induced rat epithelial ovarian carcinomas.

BACKGROUND: To investigate dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for assessing histopathological and molecular biological features in induced rat epithelial ovarian carcinomas (EOCs). METHODS: 7,12-dimethylbenz[A]anthracene (DMBA) was applied to induce EOCs in situ in 46 SD rats. Conventional MRI and DCE-MRI were performed to evaluate the morphology and perfusion features of the tumors, including the time-signal intensity curve (TIC), volume transfer constant (Ktrans), rate constant (Kep), extravascular extracellular space volume ratio (Ve) and initial area under the curve (IAUC). DCE-MRI parameters were correlated with histological grade, microvascular density (MVD), vascular endothelial growth factor (VEGF) and fraction of Ki67-positive cells and the serum level of cancer antigen 125 (CA125). RESULTS: Thirty-five of the 46 rats developed EOCs. DCE-MRI showed type III TIC more frequently than type II (29/35 vs. 6/35, p < 0.001) in EOCs. The two types of TIC of tumors had significant differences in the histological grade, MVD, expression of VEGF and Ki67, and the serum level of CA125 (all p < 0.01). Ktrans, Kep and IAUC values showed significant differences in different histological grades in overall and pairwise comparisons except for IAUC in grade 2 vs. grade 3 (all p < 0.01). There was no significant difference in Ve values among the three grade groups (p > 0.05). Ktrans, Kep and IAUC values were positively correlated with MVD, VEGF and Ki67 expression (all p < 0.01). Ve was not significantly correlated with MVD, VEGF expression, Ki67 expression and the CA125 level (all p > 0.05). CONCLUSIONS: TIC types and perfusion parameters of DCE-MRI can reflect tumor grade, angiogenesis and cell proliferation to some extent, thereby helping treatment planning and predicting prognosis.

Nitric oxide (•NO) generation but not ROS plays a major role in silibinin-induced autophagic and apoptotic death in human epidermoid carcinoma A431 cells.

Silibinin, a major active constituent of silymarin, is clinically used as a hepatoprotectant, and in recent years, it has been used for the treatment of cancer in China. Because the mechanism of silibinin action on cancer cells was still unclear, we investigated the contribution of silibinin to the induction of apoptosis and autophagy via generation of reactive oxygen species (ROS) and nitric oxide (•NO) in human epidermoid carcinoma A431 cells. Silibinin inhibited the cell growth in a dose-and time-dependent manner. Obvious autophagy was observed after treatment with different doses of silibinin. At a high dose (400 µM), silibinin induced apoptosis through both the intrinsic and extrinsic apoptotic pathways. Loss of mitochondrial membrane potential by silibinin led to mitochondrial dysfunction and decreased ROS levels, suggesting that silibinin might act as an antioxidant in this process. Furthermore, silibinin induced •NO generation in a time-and dose-dependent manner. The •NO scavenger PTIO could effectively clear •NO and exerted a minor cell protection effect through partial inhibition of silibinin-induced apoptosis and autophagy.