Estrogen and progesterone, female sex hormones, are known to play important roles in female reproductive health via their nuclear receptors. Some cancers and tumors show these female sex hormones(especially estrogen)dependent growth and development. Therefore, various types of drugs, which modulate these hormonal effects, have been developed and used for treatment of estrogen receptor(ER) and/or progesterone receptor(PR) positive cancers since 1960 s. In this decade. the researches on structures and functions of ER and PR isoforms have rapidly been promoted by the progress of molecular biology. The researches and developments of new drugs against ER and/or PR positive cancers(e.g. pure antiestrogen, progesterone receptor modulators) are also in progress. In this review, we will introduce the functions of ER and PR, endocrine therapy for ER and/or PR positive cancers, and recent researches on new compounds and natural products which show antitumor effects against ER and/or PR positive cancers.

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Histone deacetylase (HDAC) is increasingly drawing attention as a molecular target for cancer therapy. Histone acetylation plays an important role in controlling transcription by modulating chromatin structure and function. HDAC has been linked to tumorigenesis and tumor angiogenesis, and its inhibitors are currently studied clinically. This review focuses on the physiological roles of HDAC and the molecular mechanism of action of HDAC inhibitors. The coming generation of HDAC inhibitors will also be discussed.

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PI 3-kinase is known as one of the most famous lipid kinase which plays a central role in the field of growth factor-mediated signal transduction. Recent progress of molecular and developmental biology contributed to be clear numerous molecules of upstream and downstteam of PI 3-kinase. These results help us to understand the functions of PI 3-kinase and their molecular mechanisms. Furthermore, human genome draft sequence has been appeared, and several somatic mutations of the gene coding PI 3-kinase, which link to various diseases were already found. In this review, we would like to introduce the representative topics related to the PI 3-kinase pathway linking to human cancer, and current progress of our research on the relationship between malignancy of signet-ring cell carcinomas and PI 3-kinase.

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Autotaxin (ATX) is a tumor cell motility-stimulating factor, originally isolated from melanoma cell supernatants. ATX had been proposed to mediate its effects through 5'-nucleotide pyrophosphatase and phosphodiesterase activities. However, the ATX substrate mediating the increase in cellular motility remains to he identified. Here, we demonstrated that lysophospholipase D (lysoPLD) purified from fetal bovine serum, which catalyzes the production of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine(LPC), is identical to ATX. The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate. LPA mediates multiple biological functions including cytoskeletal reorganization, chemotaxis and cell growth through activation of specific G-protein-coupled receptors. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines. Moreover, we demonstrate that several cancer cell lines release significant amounts of LPC, a substrate for ATX, into the culture medium. The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine production of LPA contributes to tumor cell motility, survival and proliferation. It also provides potential novel targets for therapy of pathophysiological states, including cancer.

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Every organ or tissue is mainly composed of its characteristic epithelial cells and its stroma. Epithelial-stromal cell interaction between the epithelial cells and the surrounding stroma regulates growth and function of the highly differentiated epithelial cells and homeostasis of the tissue. Because characters of the epithelial cells and the stroma are different from each tissue, the epithelial-stromal cell interaction is specific to each tissue. Like normal tissue, solid tumor tissue is composed of tumor cells and surrounding stroma including fibroblasts, macrophages, and endothelial cells. Since most solid tumor is generated from epithelial cells, growth of the tumor cells is regulated by the surrounding stroma through diffusible factors and/or adhesion similar to normal tissue. This tumor-stromal cell interaction plays a significant role in tumor growth, invasion, and metastasis, but the molecular mechanisms underlying the interaction are still unclear due to its complexity. However, recent studies have revealed some basic backgrounds for the tumor-stromal cell interaction concerning specific tumor types. This review article has focused especially on fibroblasts among stroma and briefly summarized recent advance of the tumor-stromal cell interaction. The fibroblasts promote tumor growth in one condition, but they also suppress it in another condition. There is a chance to control the tumor growth by modulating the tumor-stromal cell interaction. The perspective for development of an antitumor drug that modulates the tumor-stromal cell interaction is also discussed.

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Establishment of chimeric antibodies and humanized antibodies has solved the problem of antigenicity of mouse monoclonal antibodies and efficacy of these antibodies has been demonstrated in a number of clinical trials. Novel antibody drugs named Rituxan and Herceptin for the indication of non-Hodgkin's lymphoma and breast cancer respectively have been evaluated as innovative drugs in oncology area. In this article, antibody technology as the basis of antibody drugs, anti-tumor mechanism of antibody, target antigens and current status of clinical trial of antibodies are introduced.

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Studies conducted at the US National Cancer Institute(NCI)and in our laboratory show that databases including the drug sensitivities of panels of many human cancer cell lines(cancer cell line-panel) provide valuable information on the molecular pharmacology of anticancer drugs. The cancer cell line-panel is a unique system where “a wet system (biological experiments)” and “a dry system (informatics)” are efficiently combined. Its characteristic is to predict the action mechanism of a testing compound. We have been using this system for drug discovery, coupled with various target-based drug screenings. We used the system to identify a novel DNA minorgroove binder, MS-247, which has inhibitory activity against topoisomerases I and II, and potent in vivo antitumor activity against various human cancer xenografts. We also discovered a potent novel telomerase inhibitor, FJ 5002, by mining our database with the COMPARE algorithm, followed by experimental validation. We investigated the gene expression profiles of the cell lines by using cDNA microarrays to find profiles determining cellular chemosensitivity and new targets for anticancer drugs. Our integrated database, including the chemosensitivities and gene expression profiles of the cell-line panel, could provide a basis for drug discovery and personalized therapy.

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