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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (1694)	7/2/2003 7:27:12 PM
From: Miljenko Zuanic	Respond to of 3044

Cancer Research 63, 3495-3502, July 1, 2003] © 2003 American Association for Cancer Research -------------------------------------------------------------------------------- Carcinogenesis Bombesin Stimulates Nuclear Factor B Activation and Expression of Proangiogenic Factors in Prostate Cancer Cells1 Lyuba Levine, Joseph A. Lucci, III, Barbara Pazdrak, Ji-Zhong Cheng, Yan-Shi Guo, Courtney M. Townsend, Jr. and Mark R. Hellmich2 Departments of Obstetrics and Gynecology [L. L., J. A. L.], Surgery [B. P., J-Z. C., Y-S. G., C. M. T., M. R. H.], and Physiology and Biophysics [M. R. H.], The University of Texas Medical Branch, Galveston, Texas 77555 The majority of deaths from prostate cancer occur in patients with androgen-insensitive metastatic disease. An important early event in the development of the metastatic phenotype is the induction of genes that promote angiogenesis, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), which are released from tumor cells into their microenvironment. Coincident with progression from prostatic carcinoma in situ to metastatic disease is an increase in the number of tumor cells exhibiting neuroendocrine (NE) differentiation. NE cells express a variety of peptide hormones, including the bombesin (BBS)-like peptide, gastrin-releasing peptide (GRP), and its cognate receptor, GRP-R. Although there is a strong positive correlation between the degree of NE differentiation and the metastatic potential of prostate cancers, a mechanistic link between increased expression of peptide hormone receptors, such as GRP-R, and proangiogenic gene expression has not been established. Here we report that BBS stimulates nuclear factor B (NFB) activation and proangiogenic gene expression in the androgen-insensitive prostate cancer cells lines, PC-3 and DU-145. In PC-3 cells, BBS stimulation of GRP-R resulted in the up-regulation of IL-8 and VEGF expression through a NFB-dependent pathway. We show that BBS treatment induced inhibitor of NFB degradation, NFB translocation to the cell nucleus, increased NFB binding to its DNA consensus sequence, and increased IL-8 and VEGF mRNA expression and protein secretion. Treatment with the proteasome inhibitor, MG-132, blocked BBS-stimulated NFB DNA binding, and IL-8 and VEGF expression and secretion. Finally, media collected from PC-3 cell cultures, after BBS treatment, stimulated an NFB-dependent migration of human umbilical vascular endothelial cells in vitro. Together, our data demonstrate a role for BBS and GRP-R in the NFB-dependent up-regulation of proangiogenic gene expression, and suggest a possible molecular mechanism linking NE differentiation and the increased metastatic potential of androgen-insensitive prostate cancers.

To: Icebrg who wrote (1694)	7/3/2003 2:05:30 AM
From: Icebrg	Read Replies (1) \| Respond to of 3044

Millennium and Xenova Initiate Phase I Clinical Trial Of MLN944 Thursday July 3, 2:00 am ET CAMBRIDGE, Mass., and SLOUGH, U.K., July 3 /PRNewswire-FirstCall/ -- Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM - News) and Xenova Group, plc (Nasdaq: XNVA - News; London Stock Exchange: XEN - News), today announced the initiation of a phase I clinical trial of MLN944 (also known as XR5944). MLN944 is a novel DNA targeting agent under investigation for the treatment of advanced cancers. The phase I clinical trial is an open label, dose-escalation study in adult patients with advanced solid tumors to evaluate the safety and tolerability, as well as pharmacokinetic properties of MLN944. The study will be conducted at three centers in the United Kingdom and will include approximately 40 patients. MLN944 is a novel DNA targeting agent that in preclinical studies has demonstrated a high level of anti-tumor activity, both in vitro and in vivo, against a number of human tumor models. In human tumor xenograft models, treatment with MLN944 caused both partial and complete regression of large established tumors. Recent data published in the Proceedings for the 2003 Annual Meeting of the American Association for Cancer Research, suggests that MLN944 acts through a novel mechanism of action distinct from other current cytotoxic agents. Further exploration into the mechanism of action is ongoing. "MLN944 is an important compound in our oncology portfolio that we believe holds great potential and is based on the Millennium commitment to breakthrough science and breakthrough medicine," said Barry Greene, general manager of oncology at Millennium. "With both the preclinical activity data and our growing understanding of the novel mechanism of action, we are optimistic that MLN944 may provide patients with an important new therapeutic option." "MLN944 has one of the best preclinical profiles we have seen both in vitro and in vivo," said David Oxlade, Xenova's Chief Executive Officer. "We are hopeful that the exciting MLN944 preclinical activity will translate into a clinical compound that helps address the clear and growing need in the marketplace for better, more efficacious cancer treatments." Millennium licensed MLN944 from Xenova Group plc in December 2001 as part of a larger collaboration including two other compounds MLN576 (XR11576) and MLN612 (XR11612). Millennium is currently funding Xenova to implement development activities associated with the program to the completion of phase II clinical trials, at which time Millennium has the right to assume development responsibility in North America. Xenova retains commercialization and development responsibility for the rest of the world. Enrollment for MLN576 is currently completing in its UK-based Phase I trials and the study data will then be reviewed to assess further development plans.