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What's New In Research - February 12, 2004
02.12.04
c-Jun NH2-terminal kinase inhibition arrests growth in multiple myeloma cells
(c) Copyright 2004 Cancer Weekly via NewsRx.com

"Although c-Jun NH2-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively," researchers in the United States report.

"Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells," wrote Teru Hideshima and colleagues at the Dana-Farber Cancer Institute. "Induction of growth arrest is mediated by upregulation of p27(Kip1), without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs)."

"SP600125 induces NF-kappaB activation in a dose-dependent fashion, associated with phosphorylation of IkappaB kinase alpha (IKKalpha) and degradation of IkappaBalpha," reported the scientists. "In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-kappaB activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-kappaB in MM cells."

Hideshima and associates published their study in Oncogene (Biologic sequelae of c-Jun NH2-terminal kinase (JNK) activation in multiple myeloma cell lines. Oncogene, 2003;22(54):8797-8801).

For additional information, contact Kenneth Anderson, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. E-mail: kenneth_anderson@dfci.harvard.edu.


Telomerase inhibition is a unique strategy for treating hematological cancers
© Copyright 2004 Cancer Gene Therapy Week via NewsRx.com

"The effects of telomerase inhibition with an oligonucleotide N3' --> P5' thiophosphoramidate (GRN163) complementary to the telomerase template region were examined on human multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines, primary MM cells, and tumor xenografts. GRN163 treatment reduced telomerase levels in all cells and induced more rapid telomeric shortening. Continuous GRN163 treatment for 7 to 14 days resulted in proliferative arrest, morphologic changes, and apoptosis characteristic of cell crisis in tumor cell lines with short (1.7-5.4 kb) but not long (9-11 kb) telomeres," scientists in the United States report.

"Intratumoral administration of GRN163 also inhibited the growth of MM and NHL xenografts established from cell lines with short telomeres (Hs602 lymphoma, 2.7 kb; CAG myeloma, 2.7 kb) and increased tumor apoptosis. However, GRN163 therapy of NHL xenografts established from cells with long telomeres (11.0 kb) had equivocal effects on tumor growth and did not induce apoptosis during this time frame," said E.S. Wang and colleagues, Memorial Sloan Kettering Cancer Center, Cell Biology Program.

"Systemic daily intraperitoneal administration of GRN163 in myeloma xenografts with short telomere lengths also decreased tumor telomerase levels and reduced tumor volumes. These data demonstrate that telomerase is important for the replication of mature B-cell neoplasia by stabilizing short telomeres, and they suggest that telomerase inhibition represents a novel therapeutic approach to MM and NHL," researchers concluded.

Wang and colleagues published their study in Blood (Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma. Blood, 2004;103(1):258-266).

For more information, contact M.A.S. Moore, Mem Sloan Kettering Cancer Center, Cell Biology Program, Laboratory Development Hematopoiesis, 1275 York Avenue, New York, NY 10021, USA.


Thalidomide treatment possibly caused multiple myeloma dedifferentiation
© Copyright 2004 Biotech Business Week via NewsRx.com

"In these cases, thalidomide treatment despite reduction of M-component was followed by disease progression and a very poor clinical outcome which was paralleled by bone marrow plasmacytosis showing marked signs of dedifferentiation, inducing us to speculate on a potential role of thalidomide on dedifferentiation of myeloma cells," wrote E. Balleari and colleagues, University of Genoa, Department of Internal Medicine.

The researchers concluded: "In our opinion, a possible dedifferentiation of MM should therefore be taken into account in MM patients treated with thalidomide when clinical course deteriorates despite reduction of M-component."

Balleari and colleagues published their study in Leukemia & Lymphoma (Possible multiple myeloma dedifferentiation following thalidomide therapy: A report of four cases. Leuk Lymphoma, 2004;45(4):735-738).

For additional information, contact E. Balleari, University of Genoa, Department of Internal Medicine, Hematology & Oncology Section, Viale Benedetto XV 6, I-16132 Genoa, Italy.


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