The gene for E3 ubiquitin ligase WWP1 is located at 8q21, a region frequently amplified in human cancers, including prostate cancer. Recent studies have shown that WWP1 negatively regulates the TGFb tumor suppressor pathway by inactivating its molecular components, including Smad2, Smad4 and TbR1. These findings suggest an oncogenic role of WWP1 in carcinogenesis, but direct supporting evidence has been lacking. In this study, we examined WWP1 for gene dosage, mRNA expression, mutation and functions in a number of human prostate cancer samples. We found that the WWP1 gene had copy number gain in 15 of 34 (44%) xenografts and cell lines from prostate cancer and 15 of 49 (31%) clinical prostate cancer samples. Consistently, WWP1 was overexpressed in 60% of xenografts and cell lines from prostate cancer. Mutation of WWP1 occurred infrequently in prostate cancer. Functionally, WWP1 overexpression promoted colony formation in the 22Rv1 prostate cancer cell line. In PC-3 prostate cancer cells, WWP1 knockdown significantly suppressed cell proliferation and enhanced TGFb-mediated growth inhibition. These findings suggest that WWP1 is an oncogene that undergoes genomic amplification at 8q21 in human prostate cancer, and WWP1 overexpression is a common mechanism involved in the inactivation of TGFb function in human cancer.

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Purpose: As combination chemotherapy of antiangiogenic agents with conventional chemotherapeutic drugs continues to evolve, an understanding of the pharmacokinetic and pharmacodynamic variables associated with optimal treatment is needed. Thus, the effect of the multitargeted tyrosine kinase inhibitor sunitinib on tumor distribution of temozolomide was investigated to evaluate conditions for optimal combination chemotherapy. Experimental Design: In mice bearing SF188V+ human glioma xenografts, measurements of temozolomide pharmacokinetic properties and sunitinib pharmacodynamic activities were evaluated, the latter including determinants for vascular normalization, including CD31, collagen IV, and a-SMA. Results: Sunitinib given in a daily dose of either 10 or 40 mg/kg orally over 14 days increased temozolomide tumor distribution, as indicated by the tumor-to-plasma AUC ratio compared with control; however, only the 10 mg/kg group reached statistical significance (P < 0.05). From the pharmacodynamic analysis, a''vascular normalization index'' incorporating the microvessel density (MVD) and protein expression of a-SMA and collagen IV was proposed as an indication of the number of tumor vessels with relatively good quality, which was found to be significantly correlated with the unbound temozolomideAUC in tumor interstitial fluid (P = 0.05). Furthermore, both sunitinib-treated groups maintained the molecular balance between angiopoietins Ang-1 and Ang-2, suggesting a critical role of angiopoietins in vascular normalization. Conclusions: Several important factors relevant to the antiangiogenic agent^induced tumor vascular normalization have been identified and incorporated into a vascular normalization index that may serve to correlate the angiogenic phenotype to the distribution of cytotoxic drugs in solid tumors.

Daodi medicinal material is produced and assembled in specific geographic regions with designated natural conditions and ecological environment, with particular attention to cultivation technique, harvesting and processing. The quality and clinical effects surpass those of same botanical origin produced from other regions. It is thus widely recognized and has long enjoyed a good reputation. Based on literature, market and field investigation on daodi medicinal materials, the historical background and reasons behind the formation and the development of daodi medicinal material are analyzed. This review clarifies the concept and rationalizes the formation of daodi medicinal material.