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Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients.
Calabro A, Oken MM, Hascall VC, Masellis AM.
Virginia Piper Cancer Institute, Abbott Northwestern Hospital, Minneapolis, MN; and Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, OH.
(Blood. 2002;100:2578-2585)

Hyaluronan (HA) is suggested to play a role in the pathophysiology of multiple myeloma. To further investigate the role of HA in this disease, we examined hyaluronan synthase (Has) gene expression and HA production in bone marrow mesenchymal progenitor cells (bmMPCs) derived from multiple myeloma patients. The relative abundance of mRNA for each HAS gene was determined using competitive reverse transcription-polymerase chain reaction (cRT-PCR), whereas HA production was detected by fluorophore-assisted carbohydrate electrophoresis (FACE). We determined the basal expression of Has isoforms in myeloma bmMPCs and then compared this expression with expression in healthy donor bmMPCs. Of the 3 Has isoforms, Has1 mRNA was expressed predominantly in myeloma bmMPCs, with expression 7.6-fold greater than Has2. Compared with normal bmMPCs, Has1 mRNA expression was 20-fold greater in myeloma bmMPCs. Normal bmMPCs predominantly expressed Has2 mRNA (8.2-fold greater than myeloma bmMPCs). Upon coculture of myeloma bmMPCs with plasma cells, Has1 transcript was strongly attenuated. FACE results show that myeloma bmMPCs synthesize 5.7-fold more HA than those from healthy donors. These data suggest that myeloma bmMPCs could be an important component of the myeloma pathophysiology in vivo by their increased expression of extracellular matrix (ECM) components relevant to plasma cell growth and survival.


Bone resorption parameters [carboxy-terminal telopeptide of type-I collagen (ICTP), amino-terminal collagen type-I telopeptide (NTx), and deoxypyridinoline (Dpd)] in MGUS and multiple myeloma.
Jakob C, Zavrski I, Heider U, Brux B, Eucker J, Langelotz C, Sinha P, Possinger K, Sezer O.
(Eur J Haematol 2002 Jul;69 (1):37-42)

Skeletal morbidity is a major problem in multiple myeloma. Histomorphometric studies have demonstrated that increased bone resorption can be present even in the absence of radiographic abnormalities. To overcome diagnostic problems in estimating the activity of bone resorption, new laboratory parameters that reflect bone metabolism accurately are urgently needed. We analyzed three parameters of osteoclastic bone destruction, i.e. deoxypyridinoline (Dpd) and amino-terminal collagen type-I telopeptide (NTx) in urine and carboxy-terminal telopeptide of type-I collagen (ICTP) in serum, of 75 patients with multiple myeloma (n = 57) or monoclonal gammopathy of undetermined significance (MGUS, n = 18) by ELISA/RIA techniques. Serum ICTP and urinary Dpd levels increased parallel to the stage of the disease and differed significantly (P < 0.001 for ICTP and P = 0.03 for Dpd) between MGUS, myeloma stage I, and myeloma in stages II and III according to Salmon and Durie. ICTP and Dpd were significantly elevated in patients with multiple myeloma in stage I compared to individuals with MGUS, while no significant difference was found for NTx. In this first study comparing the prognostic relevance of ICTP, NTx, and Dpd in multiple myeloma patients, ICTP was found to be a prognostic factor for overall survival in the Kaplan-Meier analysis (log-rank test: P < 0.03). Urinary NTx showed borderline significance (P = 0.05), and Dpd had no prognostic value in the survival analysis. Our data show that serum ICTP and urinary Dpd levels increase in parallel to advanced disease stages, and gives the first report on a significant difference in the bone resorption parameters ICTP and Dpd between individuals with MGUS and patients with myeloma in stage I. Among the bone resorption parameters studied serum ICTP was found to be the best prognostic factor for survival in multiple myeloma.


ARIAD Reports In Vivo Efficacy of First-in-Class Product Candidates to Treat the Spread of Cancer to Bone and Osteoporosis
Press Release Source: ARIAD Pharmaceuticals, Inc.
Monday September 23, 7:35 am ET

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Sept. 23, 2002-- ARIAD Pharmaceuticals, Inc. (Nasdaq: ARIA - News) today reported, for the first time, results of new preclinical studies demonstrating the efficacy of two of its lead product candidates: AP23451 to treat cancer that has spread to bone and AP23588 to treat and prevent osteoporosis.

AP23451 has a therapeutic profile that distinguishes it from available therapies for bone metastases: the drug decreases both the extent of cancer that has spread to bone and the breakdown of bone, making this product candidate a first-in-class therapy for the treatment of bone metastases. The newly presented in vivo studies are the first to show that AP23451 blocks the extent of cancer that has spread to bone. An estimated 750,000 patients worldwide die each year with bone metastases. Pre-IND studies of AP23451 are ongoing.

AP23588 also has a therapeutic profile that differentiates it from currently marketed therapies for osteoporosis: the drug causes new bone to grow and decreases the breakdown of bone, both of which produce increased bone strength and mass, making this product candidate a first-in-class therapy for the prevention and treatment of osteoporosis. Available drugs for osteoporosis generally affect only a portion of the bone remodeling process: they either block bone breakdown by osteoclasts or stimulate bone formation by osteoblasts. None of these therapies achieves both effects - the optimal profile for a novel osteoporosis treatment. An estimated 50 million individuals worldwide have osteoporosis.

The latest data are being presented at the Twenty-fourth Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) in San Antonio, Texas and the International Symposium on Signal Transduction Modulators in Cancer Therapy in Amsterdam, Netherlands, both of which take place this week.

"Cancer that has spread to bone is one of the major causes of morbidity and mortality in patients with breast, colon, and lung cancer, and current treatments for bone metastases have clinical limitations. We believe that AP23451 may represent a compelling alternative to available therapies," said Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD.

Dr. Berger added, "After an extensive drug discovery effort, the latest results on AP23588 provide a clear path to designation of our osteoporosis product candidate for clinical development - an important milestone in the evolution of our product development portfolio."

Abstracts of the ASBMR presentations, Nos. 1145 by Boyce et al and SU377 by Xing et al, are available online at the website for the annual meeting. Further information about the International Symposium on Signal Transduction Modulators in Cancer Therapy can be found on the web at http://www.nddo.org/page_include_stm2002.shtml.

ARIAD is engaged in the discovery and development of breakthrough medicines that regulate cell signaling with small molecules. The Company is developing a comprehensive approach to the treatment of cancer and blood diseases and has seven product candidates in development. ARIAD also has an exclusive license to pioneering technology and patents related to the discovery, development and use of drugs that regulate NF-(kappa)B cell-signaling activity, which has been implicated in many major diseases.


A molecular compendium of genes expressed in multiple myeloma
Jaime O. Claudio, Esther Masih-Khan, Hongchang Tang, Jason Goncalves, Michael Voralis, Zhi Hua Li, Vincent Nadeem, Eva Cukerman, Ofella Francisco-Pabalan, Choon Chin Liew, James R. Woodgett, and A. Keith Stewart
For reprints contact: A. Keith Stewart, Princess Margaret Hospital, University Health Network, 610 University Avenue. Room 5-126, Toronto ONTARIO, M5G 2M9 CANADA
(BLOOD. 2002; 100: 2175-2186)

We have created a molecular resource of genes expressed in primary malignant plasma cells using a combination of cDNA library construction, 5' and single-pass sequencing, bioinformatics, and microarray analysis. In total, we identified 9732 non redundant expressed genes. This dataset is available as the Myeloma Gene Index .

In summary, our expressed gene catalog and myeloma enriched microarray contains numerous genes of unknown function and may complement other commercially available arrays in defining the molecular portrait of this hematopoietic malignancy.


2 Methoxyestradiol overcomes drug resistance in multiple myeloma cells
Dhaminder Chauhan, Laurence Catley, Teru Hideshima, Guilan Li, Richard Loblanc, Deepak Gupta, Martin Sattler, Paul Richardson, Robert L. Schlossman, Klaus Podor, Edie Weller, Nikhil Munshi, and Kenneth Anderson.
For reprints contact: Kenneth C. Anderson, Dana Farber Cancer Institute, 11 Binney Street, Boston MA 02215
(
BLOOD. 2002; 100:2187-2194)

2-Methoxyestradiol (2ME2) an estrogen derivative, induces growth arrest and apoptosis in leukemia cells and is antiangiogenic. In this study, we demonstrate that 2ME2 inhibits growth and induces apoptosis in multiple myeloma (MM) cells lines and patient cells. Signficantly, 2ME2, also inhibits growth and induces apoptosis in MM cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40 and Dox-6), and dexamethasone (MM.1R). In contrast to its effects on MM cells, 2ME2 does not reduce the survival of normal peripheral blood lymphocytes.

Finally, 2ME2, inhibits MM cell growth, prolongs survival, and decreases angiogenesis in a murine model. These studies, therefore, demonstrate that 2ME2 mediates anti-MM activity directly on MM cells and in the BM microenvironment. They provide a framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and to improve outcome in MM.


Role for macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta in the development of osteolytic lesions in multiple myeloma.
Masahiro Abe, Kenji Hiura, Javier Wilde, Keiji Moriyama, Toshihiro Hashimoto, Shuji Ozaki, Shingo Wakatsuki, Masaaki Kosake, Shinsuke Kido, Dalsuke Inoue, and Toshio Matsumoto.
(
BLOOD, 2002; 100:2195-2202)
For reprints contact:: Daisuke Inouo, First Department of Internal Medicine, University of Tokushima School of Medicine, 3-18-15 Kuramoto-cho. Tokushima 770-8503, Japan.

Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milleu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, in mm cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1 alpha and MIP-1 beta correlated well with the ability of myeloma cells to enhance osteociastic bone resorption both in vitro and in vivo as well as in MM patients.

We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1 alpha and MIP-1 beta induce expression of receptor activator of nuclear factor-k beta (RANK) ligand by stromal cells thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1 alpha and MIP-1 beta may be major osteoclast-activating factors produced by MM cells.


Polymorphisms and the tumor necrosis factor-alpha gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma
Kal Noben, Joannis Mytillineos, Thomas M. Moehler, Astrid Preiss, Alwin Kraemer, Anthony D. Ho, Gerhard Opeiz, and Hartmut Goldschmidt
For reprints contact:: Anthony D. Ho, Department of Internal Medicine V. University of Heidelberg, Hospitalsir 3, Heidelberg, GERMANY
(
BLOOD, 2002;100: 2263-2265)

Thalidomide (THAL) is able to block the production of tumor necrosis factor-alpha (TNT-alpha) by human monocytes in a dose-dependant manner. It has been speculated that the suppression of TNF-alpha expression is the major mechanism of action of Thal in a variety of diseases. In multiple myeloma, (MM), TNT-alpha is involved in the generation of malignant plasma cells, as monoclonal plasma cells were produced when mononuclear cells from myeloma patients were exposed to TNF-alpha and interleukin-4 in vitro. In addition, TNF-alpha has stimulatory effects on plasma cell growth by triggering the secretion of interleukin-6 and shows proangiogenic properties in vitro. However, thus far it is not clear whether the anti-TNF-alpha effect of Thal contributes to its efficacy in MM.

The aim of this study was to investigate the role of polymorphisms of the TNF-alpha gene promoter at positions -308 and -239 of TNF-alpha production in MM. In addition, we studied the effect of TNF-alpha promoter polymorphisms on the outcome after Thal therapy in 81 pts. with refractory and relapsed MM.