The number of published studies on peritoneal dissemination of scirrhous gastric carcinoma is very small as a result of the unavailability of highly reproducible animal models. Orthotopic implantation of HSC-44PE and HSC-58 (scirrhous gastric carcinoma-derived cell lines) cells into nude mice led to dissemination of the tumor cells to the greater omentum, mesenterium, peritoneum and so on, and caused ascites in a small number of animals. Cycles of isolation of the ascitic tumor cells and orthotopic inoculation of these cells were repeated in turn to animals. This was to isolate highly metastatic cell lines with a strong capability of inducing the formation of ascites (44As3 from HSC-44PE; 58As1 and 58As9 from HSC-58).

ZD6474 is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 inhibits angiogenesis and growth of a wide range of tumor models in vivo. Gefitinib ("Iressa") is a selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation. Here, the ability of gefitinib and ZD6474 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro, and a strong correlation was noted between the IC 50 values of gefitinib and ZD6474 (r ‫؍‬ 0.79). No correlation was observed between the sensitivity to ZD6474 and the level of EGFR or VEGFR expression. The NSCLC cell line PC-9 was seen to be hypersensitive to gefitinib and ZD6474, and a small (15-bp) in-frame deletion of an ATP-binding site (exon 19) in the EGFR was detected (delE746-A750 -type deletion). To clarify the involvement of the deletional mutation of EGFR in the cellular sensitivity to ZD6474, we examined the effect of this agent on HEK293 stable transfectants expressing deletional EGFR that designed as the same deletion site observed in PC-9 cells (293-p⌬15). These cells exhibited a 60-fold higher sensitivity to ZD6474 compared with transfectants expressing wild-type EGFR. ZD6474 inhibited the phosphorylation of the mutant EGFR by 10-fold compared with cells with wild-type EGFR. In conclusion, the findings suggested that a small in-frame deletion in the EGFR increased the cellular sensitivity to ZD6474.

Angiogenesis is an essential process for tumor growth and is regulated by tumor-derived angiogenic cytokines. Osteopontin (OPN) is one of the cytokines produced by various tumor cells and is suggested to be involved in angiogenesis by upregulating endothelial cell migration in cooperation with vascular endothelial cell growth factor (VEGF). To provide evidence of OPN involvement in a causal role in tumor angiogenesis, we generated a stable transfectant from murine neuroblastoma C1300 cells to constitutively secrete high levels of murine OPN. The OPN mRNA expression and protein secretion were confirmed by RT-PCR and ELISA, respectively. The biological activity of secreted OPN was deter- Angiogenesis, the formation of new blood vessels, is essential for tumor growth and metastasis. 1,2 Previous studies have indicated that this angiogenesis process is mediated by numerous angiogenic factors that are produced by tumor cells. 3,4 Non-vascularized tumor cells secrete angiogenic cytokines that diffuse in the direction of pre-existing blood vessels. These cytokines activate quiescent vascular endothelial cells, enabling them to proliferate and migrate toward the tumor. 5,6 In addition, cell adhesive receptors including ␣v-integrins facilitate the endothelial cell migration by interacting with adhesive proteins in the extra-cellular matrix (ECM). 7 Thus, angiogenesis process depends on the cooperation of angiogenic cytokines and cell adhesive events.Osteopontin (OPN) is a phosphoprotein that binds to ␣v integrins at the arginine-glycine-asparatic acid (RGD) motif of the central portion and exerts cell adhesion and migration activity. 8 -11 OPN is secreted from various cancer cell lines and is postulated to be related with malignant transformation. 12 When ras-transformed fibroblasts were transfected with an antisense OPN RNA, their tumorigenic and malignant growth were suppressed significantly. 13 OPN has also been revealed to be overexpressed in human cancers, 14,15 and serum levels of OPN were substantially elevated in patients with metastatic cancer. 16 Thus OPN is postulated to be related with cancer progression.OPN has been considered to be an adhesive protein due to its integrin binding activity. However, OPN has many other novel properties, suggesting that it may act as a cytokine in various situations. [17][18][19][20][21][22] Recently, much interest has been focused on the biological role of OPN in the pathogenesis of angiogenesis. For example, Senger et al. 23 reported that OPN in cooperation with VEGF promotes vascular endothelial cell migration via ␣v integrin, suggesting that OPN may be involved in angiogenesis. Shijubo et al. 24 demonstrated that coexpression of OPN and VEGF is closely associated with angiogenesis and poor prognosis in Stage I lung adenocarcinoma. Some other researchers have also suggested the possible role of OPN in angiogenesis. [25][26][27] However, there has been no studies that established the causal role for OPN in tumor angiogenesis.The purpose of our study was to determine and p...

No abstract

The major problem in lung cancer chemotherapy is the emergence of inherent and acquired drug resistance of the cancer cells. Establishment of drug-resistant sublines and comparative investigations of such cell lines with their parental cells to determine their molecular, biologic, and biochemical properties are important research strategies. Genetic changes in tumor cells may induce changes in their biochemical properties and chemosensitivity. Many mechanisms that render tumor cells resistant have been identified, and they have provided new molecular targets for surrogate markers to predict chemosensitivity. The new categories of anticancer drugs, such as topoisomerase I inhibitors and taxanes, and non-cytotoxic new drugs, have been introduced clinically. It is important to define the molecular determinants of resistance to these drugs. The development of an appropriate model for overcoming drug resistance is one of the important issues that should be solved before carrying out further clinical trials.