Long-term exposure to elevated levels of circulating TIMP-1 but not mammary TIMP-1 suppresses growth of mammary carcinomas in transgenic mice.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates matrix metalloproteinase activity, acts as a growth stimulator and inhibits apoptosis. We developed transgenic mice to evaluate the relevance of circulating versus mammary TIMP-1 in mammary carcinogenesis. The transgene was placed under the control of the albumin (Alb) promoter for the production of large amounts of TIMP-1 in the liver and release into the systemic circulation to achieve chronically elevated blood levels. The initial 7,12-dimethylbenz[a]anthracene (DMBA) mammary carcinogenesis study showed greatly decreased tumor incidence in heterozygous Alb-TIMP-1 mice (25%), compared with their wild-type (wt) littermates (83.3%). Metastatic mammary carcinomas were induced in the Alb-TIMP-1 mice through breeding with mice expressing the polyomavirus Middle T antigen (MT) under the control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Both the mammary tumor burden and the incidence of lung metastases were lower in the Alb-TIMP-1/MMTV-MT mice than their MMTV-MT littermates. Analysis of the Alb-TIMP-1/MMTV-MT tumors showed evidence of decreased proliferative activity and inhibition of apoptosis, whereas microvascular density was not affected. Transgenic expression of TIMP-1 in mammary epithelial cells was accomplished by using MMTV-LTR. In contrast to the Alb-TIMP-1 mice, there was insignificant difference in the growth of both DMBA- and MT-induced mammary tumors between heterozygous MMTV-TIMP-1 mice and their wt littermates. The MT-induced mammary tumors of the MMTV-TIMP-1 mice were separated into 'low' and 'high' TIMP-1 expressing groups. The 'high' TIMP-1 expressing tumors exhibited significantly higher proliferative activity than the tumors of the MMTV-MT only mice, whereas the number of apoptotic cells and microvascular density were not different. The findings of this study show that circulating TIMP-1, but not mammary-derived TIMP-1, has growth suppressive effects on DMBA and MT-induced mammary carcinomas.

Patentability and maximum protection of intellectual property in proteomics and genomics.

The patenting of inventions in the proteomics and genomics fields has been prolific in the last few years and should continue in that vein for some years to come. The ingenuity by which inventions can be claimed increases so that even computerized methods for finding useful drugs based on the underlying genomic and proteomic information find their way into patents. However, with the increasing number of patents invalidated and the increasing number of exceptions to patent infringement; the value of new biotechnology patents is being whittled away. First, it may be hard to find potential infringers who improperly practice the claimed invention. Second, these potential infringers may practice in areas of the world where there is no patent protection. Third, the practice may be held by a court not to be infringing activity because it has as its aim the development of a new drug. Finally, the claims may be held invalid for lack of written description or enablement as the courts find mechanisms or reasons to narrow the allowable claims. With this setting, we must consider what can be done to best protect this new generation of inventive activity. Moreover, we must consider the possible demise of the drug pipeline should this trend to narrow protection continue.