Stressed out? It turns out B cells need to be stressed to ramp up their metabolic capacity to make antibodies in response to infection.
(Copyright 2003 Immunotherapy Weekly via NewsRx.com
In the April 2003 issue of Nature Immunology, researchers at Harvard link the cellular stress response, known as the unfolded protein response, to the terminal differentiation of B cells to turn into antibody-producing plasma cells. The results provide new clues about how diseases, such as multiple myeloma, arise and may lead to new therapeutic targets.
Plasma cells are antibody factories, capable of synthesizing and secreting vast amounts of specific antibodies into the bloodstream. However, precursors of these cells need to be alerted to increase their production capacity. Glimcher and colleagues showed B cells make small amounts of antibody, but these molecules fail to fold properly and signal the stress response. During this same period, B cells increase their expression of a gene called XBP-1, which is the master switch for plasma cell differentiation. However, the form of XBP-1 message produced in the absence of the stress response encodes a nonfunctional protein.
The new data show how this stress response triggers splicing of the XBP-1 message to encode the functional XBP-1 protein, which then turns on genes that are required for plasma cell differentiation and increased antibody production. Thus, aberrant activation of XBP-1 might contribute to the development of multiple myeloma, the malignant counterpart of plasma cells.
Myeloablative stem cell transplantation adds little benefit to high-dose chemotherapy for multiple myeloma patients.
Copyright 2003 Hematology Week via NewsRx.com
Investigators in the Netherlands "compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma."
"There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma" who participated in this study, according to C. M. Segren and colleagues at Leiden University.
Patients "were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD)" to receive either "melphalan 140 mg/m2 administered intravenously in two doses of 70 mg/m2 (intermediate dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132)," Segren and coworkers said. "Interferon-alpha-2a was given as maintenance."
"Of the eligible patients, 79% received both cycles of IDM and 9% of allocated patients actually received myeloablative treatment," the report indicated. "The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group."
"CR was significantly higher after myeloablative therapy (13% versus 29%; P = .002)," study data showed. "With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different" between the two treatment cohorts, although "time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P = .04)."
"The overall survival (OS) was not different (50 months versus 47 months; P = .41)," the researchers noted.
"Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone," they concluded. "However, it did not result in a better EFS and OS."
Segeren and coauthors published their study in Blood (Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood, 2003;101(6):2144-2151).
For more information, contact C.M. Segeren, Leiden University, Medical Center, Department of Clinical Oncology, K1-P, P.O. Box 9600, NL-2300 RC Leiden, the Netherlands.
Drug resistant multiple myeloma may be treated with the farnesyl transferase inhibitor, FTI-277.
Copyright 2003 Clinical Oncology Week via NewsRx.com
"Mutations of the ras gene are among the most commonly identified transforming events in human cancers, including multiple myeloma. Farnesyl transferase inhibitors (FTI) were developed to prevent Ras processing and induce cancer cell death. Several FTIs are in phase II and one is in phase III clinical trials," scientists in the United States report.
"Preclinically, most of the focus has been on solid tumors, and the effects of FTIs in multiple myeloma have not been investigated. In this study we examined the cytotoxic activity and inhibition of Ras processing in 3 myeloma cell lines with differing Ras mutation status. H929 cells with activated N-Ras were more sensitive to FTI-277 treatment than 8226 and U266 cells with activated K-Ras or wild-type Ras, respectively. A combination of FTI-277 and a geranylgeranyl transferase I inhibitor (GGTI)-2166 inhibited K-Ras processing and enhanced cell death in 8226 cells. U266 cells and Bcl-x(L) transfectants were equally sensitive to FTI-277 treatment," wrote S.C.E. Bolick and colleagues.
The researchers concluded: "Similarly, 8226 cells selected for resistance to various chemotherapeutic agents, which resulted in either P-glycoprotein overexpression, altered topoisomerase II activity, or elevated glutathione levels, were equally sensitive to FTI-277. These preclinical studies suggest that prenylation inhibitors may represent new therapeutic agents for the treatment of refractory or drug resistant multiple myeloma."
Bolick and colleagues published their study in Leukemia (The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. Leukemia, 2003;17(2):451-457).
For more information, contact W.S. Dalton, University S Florida, College Med, H Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Dr., Tampa, FL 33612, USA.
Neovastat (AE-941; AEterna), an antiangiogenic drug isolated from marine cartilage, appears suitable for long-term use, report cancer researchers in Canada.
Copyright 2003 Angiogenesis Weekly via NewsRx.com
Neovastat "interferes with several steps associated with the development of angiogenesis through its ability to induce endothelial cell apoptosis, and to inhibit matrix metalloproteinase activities and vascular endothelial growth factor-mediated signaling pathways, suggesting that Neovastat behaves as a multifunctional antiangiogenic drug," said wrote D. Ginqras and colleagues. "Neovastat is orally bioavailable, and shows significant antitumor and antimetastatic properties in animal models."
They noted that the drug has "an excellent safety profile with few side effects." Some of the 800+ patients "exposed to Neovastat" have received it for over four years.
"This indicates that Neovastat is suitable for long-term use, either alone or in combination with other anticancer therapies," stated Ginquas and colleagues.
"Accordingly," they noted, "Neovastat is currently under evaluation in three pivotal clinical studies with two Phase III clinical trials in patients with lung and renal carcinoma, and a Phase II clinical trial in patients with multiple myeloma is ongoing."
Ginqras and coauthors published their study in Anti-Cancer Drugs (Neovastat - A novel antiangiogenic drug for cancer therapy. Anti-Cancer Drug, 2003;14(2):91-96).
For additional information, contact R. Bebliveau, UQAM, Center Cancerol Charles Bruneau, Laboratory Med Molecular Ste. Justine, 3175 Chemin Cote Ste. Catherine, Montreal, PQ H3T 1C5, Canada.