Suppression of hepatic tumor growth and metastasis by metronomic therapy in a rat model of hepatocellular carcinoma

Although continuous low-dose (metronomic [MET]) therapy exerts anti-cancer efficacy in various cancer models, the effect of long-term MET therapy for hepatocellular carcinoma (HCC) remains unknown. This study assessed the long-term efficacy of MET on suppression of tumor growth and spontaneous metastasis in a rat model of HCC induced by administration of diethylnitrosamine for 16 wk. The rats were divided into 3 groups: MTD group received intraperitoneal (i.p.) injections of 40 mg/kg cyclophosphamide on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received i.p. injections of saline and 20 mg/kg cyclophosphamide twice a week, respectively. Anti-tumor and anti-angiogenic effects and anti-metastatic mechanisms including matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were evaluated. Twelve wk of MET therapy resulted in a significant reduction in intrahepatic tumors than control or MTD therapy. The MET group had fewer proliferating cell nuclear antigen-positive cells and decreased hypoxia-inducible factor-1alpha levels and microvessel density. Lung metastases were detected in 100%, 80%, and 42.9% in the control, MTD, and MET groups, respectively. MET therapy significantly decreased expression of TIMP-1, MMP-2 and -9. For mediators of pro-MMP-2 activation, MET therapy induced significant suppression in the TIMP-2 and MMP-14 level. The survival in the MET group was significantly prolonged compared to the control and MTD groups. Long-term MET scheduling suppresses tumor growth and metastasis via its potent anti-angiogenic properties and a decrease in MMPs and TIMPs activities. These results provide a rationale for long-term MET dosing in future clinical trials of HCC treatment.

Does thymidine phosphorylase correlate with angiogenesis in intraductal carcinoma of the breast?

To determine the association between thymidine phosphorylase [TP] and angiogenesis, and other conventional prognostic markers. We also evaluated interobserver and intraobserver reliability for TP expression in ductal carcinoma, to achieve a more consistent results. Our study included all cases diagnosed in Adnan Menderes University Medical Faculty Hospital, Aydin, Turkey as invasive ductal carcinoma or ductal carcinoma in situ [DCIS] with proven component of [>30%], between January 2003 and February 2005. The total number of the cases was 27 and their median age was 50 years. All sections were stained using monoclonal antibody-TP and examined at x40 magnification. Either nuclear or cytoplasmic staining was accepted as positive. The histoscore [H-score] was calculated for each specimen. The tumor stromal vascularity was assessed by monoclonal anti-CD34; and areas of intense vascularization were determined. Conventional immunohistochemical markers such as c-erb B2, Ki-67, estrogen and progesterone receptors and p53 were also applied to all slides. Three pathologists blindly examined each slide under 10 high-power fields [10 HPF] for 2 times in a 2 months period. There was no significant association between stromal vascularity and TP staining of cancer cells [p=0.1] and no correlation was determined between H-scores for TP staining in ductal carcinoma and DCIS components [p=0.5]. There was no significant correlation noted between stromal and periductal vascularity with the anti-CD34 antibody was used. No significant correlation was identified between the TP H-score and stromal or periductal vascularity