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What's New In Research - August 22, 2003
08.22.03
DNA microarrays are new molecular tools to investigate malignant plasma cells.
(c) Copyright 2003 Health & Medicine Week via NewsRx.com

According to a study from France, "Although multiple myeloma (MM) is a unique entity, a marked heterogeneity is actually observed among the patients, which has been first related to immunoglobulin (Ig) types and light chain subtypes and more recently to chromosomal abnormalities.

"To further investigate this genetic heterogeneity, we analyzed gene expression profiles of 92 primary tumors according to their Ig types and light chain subtypes with DNA microarrays," wrote F. Magrangeas and colleagues, University Hospital, INSERM.

"Several clusters of genes involved in various biologic functions such as immune response, cell cycle control, signaling, apoptosis, cell adhesion, and structure significantly discriminated IgA- from IgG-MM," the researchers stated.

"Genes associated with inhibition of differentiation and apoptosis induction were up-regulated while genes associated with immune response, cell cycle control, and apoptosis were down-regulated in IgA-MM," the researchers wrote.

"According to the expression of the 61 most discriminating genes, BJ-MM represented a separate subgroup that did not express either the genes' characteristic of IgG-MM or those of IgA-MM at a high level. This suggests that transcriptional programs associated to the switch could be maintained up to plasma cell differentiation," the researchers stated.

"Several genes whose products are known to stimulate bone remodeling discriminate between kappa- and lambda-MM. One of these genes, Mip-1alpha, was overexpressed in the kappa subgroup," they added.

In addition, we established a strong association (P = .0001) between kappa subgroup expressing high levels of Mip-1alpha and active myeloma bone disease," the researchers stated.

The researchers concluded: "This study shows that DNA microarrays enable us to perform a molecular dissection of the bioclinical diversity of MM and provide new molecular tools to investigate the pathogenesis of malignant plasma cells."

Magrangeas and colleagues published their study in Blood (Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood, 2003;101(12):4998-5006).

For more information, contact S. Minvielle, University Hospital, INSERM, U463, Biology Institute, Department of Clinical Hematology, 9 Quai Moncousu, F-44095 Nantes 1, France.


CLL and MM may have different mechanisms of cell survival.
(c) Copyright 2003, Biotech Week via NewsRx.com

"We compared gene expression in purified tumor cells from untreated patients with chronic lymphocytic (CLL) (n=24) and newly diagnosed multiple myeloma (MM) (n=29) using the Affymetrix HuGeneFL microarray with probes for approximately 6800 genes," scientists in the United States report.

"Hierarchical clustering analysis showed that CLL and MM have distinct expression profiles (class prediction). Gene and protein expression (measured by flow cytometry) correlated well for CD19, CD20, CD23, and CD138 in CLL and MM, but not for immunoglobulin light chain, CD38 and CD79b in CLL, or CD45 and CD52 in MM," wrote C.S. Zent and colleagues, Mayo Clinic, Division of Hematology.

The researchers concluded: "CLL and MM differentially expressed 18% of 130 apoptosis related genes, suggesting differences in mechanisms of cell survival."

Zent and colleagues published their study in Leukemia Research (The distinct gene expression profiles of chronic lymphocytic leukemia and multiple myeloma suggest different anti-apoptotic mechanisms but predict only some differences in phenotype. Leuk Res, 2003;27(9):765-774).

For additional information, contact C.S. Zent, Mayo Clinic, Division of Hematology, 200 1st St. SW, Rochester, MN 55905, USA.


Targeted Therapy; A peptide phage library probe reveals some have myeloma-binding capacity
(c) Copyright 2003 Cancer Weekly via NewsRx.com

Some synthetic peptides appear to be capable of binding myeloma cell immunoglobulins, thus pinpointing some possibly useful myeloma-targeting agents.

"Human myeloma proteins (HMPs) from 10 patients with multiple myeloma (MM) were used to affinity-select peptides from a random phage-display peptide library. Binding peptides were identified for the 10 analyzed antibodies (8 immunoglobulin G (IgG) and 2 immunoglobulin A (IgA)). The specificity of the binding was confirmed by competitive experiments using phages and chemically synthesized peptides," researchers in France report.

"Interestingly, some phage-displayed peptides were immuno-selected with HMPs isolated from different patients. Sequence alignments and homology searches revealed a significant homology with human proteins (e.g. neural cell adhesion proteins) and pathogen-derived proteins (e.g. herpes simplex virus capsid proteins)," wrote A. Dybwad and coauthors.

The researchers concluded: "The selected peptides could be useful as targeting agents for myeloma cells expressing surface immunoglobulins."

Dybwad and colleagues published their study in Scandinavian Journal of Immunology (Probing the specificity of human myeloma proteins with a random peptide phage library. Scand J Immunol, 2003;57(6):583-590).

For additional information, contact M. Zouali, Institute Rech Biomedical Cordeliers, Unite Immunopathol Humaine, INSERM, U430, 15 Rue Ecole Med, F-75006 Paris, France


Anticancer Drugs; Study of current multiple myeloma therapy will lead to better drugs
(c) Copyright 2003 Cancer Weekly via NewsRx.com

Study of present agents used to combat multiple myeloma that are not fully effective therapy will lead to the knowledge of apoptosis, cell survival, and resistance; paving the way to better drug development.

"Multiple myeloma (MM), a hematologic malignancy, remains fatal despite all available therapies. Initial treatment with conventional drugs effectively induces MM cell death/apoptosis; however, prolonged drug exposures results in the development of de novo chemoresistance. Because MM is a bone marrow (BM) cancer, the progression of disease and drug efficacy is highly influenced by the BM microenvironment," scientists in the United States report.

"Novel agents, such as proteasome inhibitors (PS-341), 2-methoxyestradiol (2ME2), thalidomide and its immunomodulatory derivatives (IMiDs), and histone deacetylase (HDAC) inhibitors target the MM cell in its BM microenvironment; thereby enhancing anti-MM activity as well as preventing development of drug resistance," wrote D. Chauhan and colleagues.

The researchers concluded: "The transcriptional events and signaling pathways, which mediate these responses in MM cells are now being delineated, and may serve to identify novel therapeutic targets based upon interrupting MM cell growth or triggering MM cell death."

Chauhan and colleagues published their study in Apoptosis (Mechanisms of cell death and survival in multiple myeloma (MM): Therapeutic implications. Apoptosis, 2003;8(4):337-343).

For additional information, contact K.C. Anderson, Dana Farber Cancer Institute, M557, 44 Binney St., Boston, MA 02215, USA.


Bone marrow angiogenesis may promote plasma cell migration in multiple myeloma
(c) Copyright 2003 Angiogenesis Weekly via NewsRx.com

According to a study from the United States, "bone marrow (BM) angiogenesis is increased in multiple myeloma (MM) and has prognostic significance. The presence of circulating plasma cells (PCs) in MM is associated with a poorer prognosis. We examined BM biopsies obtained at diagnosis of MM for angiogenesis, and correlated the microvessel density (MVD) with the presence of circulating PCs."

"There was a positive correlation between the absolute number of circulating PCs and the mean MVD. This relationship was independent of the disease activity and of the PC burden in the marrow," reported S. Kumar and colleagues, Mayo Clinic, Division of Hematology and Internal Medicine.

"The increased angiogenesis may promote plasma cell proliferation and enable PC migration into the circulation," researchers suggested.

Kumar and colleagues published the results of their research in British Journal of Haematology (Bone marrow angiogenesis and circulating plasma cells in multiple myeloma. Br J Haematol, 2003;122(2):272-274).

For additional information, contact S.V. Rajkumar, Mayo Clinic, Division of Hematology & Internal Medicine, 200 1st St. SW, Rochester, MN 55905, USA.


Soluble serum factors can index activity during antiangiogenic therapy
(c) Copyright 2003 Cancer Weekly via NewsRx.com

According to a study from Germany, "antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. VEGF (vascular endothelial growth factor) is known to be the most important proangiogenic factor, necessary for the development of new tumor vessels. Specific inhibitors of the VEGF receptor tyrosine kinases, like PTK787/ZK222584 (PTK/ZK), have shown antitumoral and antiangiogenic activity in several animal models."

"Ongoing early clinical trials with antiangiogenic compounds reveal the need for diagnostic methods to detect their biological activity. Proangiogenic growth factors like VEGF and bFGF (basic fibroblast growth factor), soluble variants of proangiogenic receptors like sFLT-1 and sTIE-2, as well as endothelial activation markers like sE-Selectin, can be measured in the serum and plasma of patients by the ELISA technique," reported J. Drevs and colleagues, Albert Ludwigs University Hospital, Tumor Biology Center.

"They were detected in various malignant diseases to assess their use as surrogate markers in tumor angiogenesis. In different clinical Phase I trials with antiangiogenic compounds, these soluble markers were used to detect dose levels for biological activity."

"Soluble markers of tumor angiogenesis could be used as prognostic markers in various malignancies like colon cancer or multiple myeloma. Furthermore, they correlated with disease activity, prognosis and imaging techniques for the detection of vascular changes," noted researchers.

"In clinical Phase I trials with specific inhibitors of the VEGF receptor tyrosine kinases, VEGF serum levels increased in patients treated with higher doses, indicating increasing tumor hypoxia. Taking results from imaging techniques such as dynamic enhanced MRI into account, optimal doses for biological activity could be concluded."

"New biological treatment techniques will need new diagnostic methods to assess their specific biological activity in patients. Soluble markers and imaging techniques are useful tools for the detection of hypoxia under antiangiogenic treatment. Nevertheless, these techniques are still experimental. Therefore, further clinical evaluation is necessary," Drevs stated.

Drevs and colleagues published the results of their research in Anticancer Research (Soluble markers for the detection of hypoxia under antiangiogenic treatment. Anticancer Res, 2003;23(2A):1159-1161).

For additional information, contact J. Drevs, Albert Ludwigs University Hospital, Tumor Biology Center, Breisacherstr 117, D-79106 Freiburg, Germany.


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