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What's New in Research - November 19, 2002
11.19.02

Dosimetry and toxicity of Quadramet for bone marrow ablation in multiple myeloma and other haematological malignancies
Marissa L. Bartlett1, Myles Webb1, Simon Durrant2, A. James Morton2, Roger Allison2 and David J. Macfarlane1
1Department of Nuclear Medicine, Royal Brisbane Hospital, Herston, Queensland, Q4209, Australia
2Division of Oncology, Royal Brisbane Hospital, Herston, Queensland, Australia

Abstract. Standard treatment regimens for haematological malignancies include myeloablative chemoradiotherapy and subsequent rescue by stem cell transplantation. However, these treatment regimens have significant associated mortality and morbidity, and disease recurrence remains a problem. One alternative approach is the targeted delivery of radiotherapy to the marrow using a bone-seeking agent labelled with an appropriate radioisotope, with the aim of delivering a potentially ablative radiation dose to marrow while minimising non-haematological toxicity. Pharmacokinetics and radiation dosimetry for a commercial preparation of samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet) were evaluated in 43 tracer (average dose 740 MBq) studies of 42 patients with haematological malignancies. Measurements of 24-h retention were also available following infusion of 18-48 GBq in 15 patients. Quadramet cleared rapidly from the tissue, with a median biological half-life of 1.4 h. Activity taken up by the skeleton was firmly bound, with activity decreasing according to physical half-life at 24 h in 29 of the 43 cases. The percentage activity retained in the skeleton at 24 h with tracer doses was high (62%±13%), although this decreased to approximately 30% with therapy infusions. Because of this decrease in retention, the maximum feasible therapy activity for this formulation of Quadramet is 35 GBq. Median absorbed marrow radiation dose was 0.78 Gy/GBq in tracer studies: the decreased retention at high activities means that this corresponds to a median dose of 12 Gy for 35 GBq administered activity. It is possible to use 24-h retention as a rough guide to marrow dose in individual patients. In tracer studies, median bladder radiation dose was 0.22 Gy/GBq and radiation dose to the liver was very conservatively estimated at 0.2 Gy/GBq. After therapy infusions of up to 50 GBq in 37 patients, non-haematopoietic toxicity was not seen in any patient. In addition, myelosuppression was achieved without evidence of myelofibrosis. The residual dose rate to marrow fell to a level acceptable for stem cell re-infusion by 2 weeks after administration.


The Cyclin-dependent Kinase Inhibitor Flavopiridol Induces Apoptosis in Multiple Myeloma Cells through Transcriptional Repression and Down-Regulation of Mcl-1.
Gojo I, Zhang B, Fenton RG.
Greenebaum Cancer Center, University of Maryland Medical System, Baltimore, Maryland 21201.
Clin Cancer Res 2002 Nov; 8(11):3527-38

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of malignant plasma cells with slow proliferative rate but enhanced survival. MM cells express multiple Bcl-2 family members, including Bcl-2, Bcl-XL, and Mcl-1, which are thought to play a key role in the survival and drug resistance of myeloma. The cyclin-dependent kinase inhibitor flavopiridol has antitumor activity against hematopoietic malignancies, including CLL, in which induction of apoptosis was associated with reduced expression of antiapoptotic proteins. Therefore, we sought to characterize the effect of flavopiridol on the proliferation and survival of myeloma cells and to define its mechanisms of action. Treatment of MM cell lines (8226, ANBL-6, ARP1, and OPM-2) with clinically achievable concentrations of flavopiridol resulted in rapid induction of apoptotic cell death that correlated temporally with the decline in Mcl-1 protein and mRNA levels. Levels of other antiapoptotic proteins did not change. Overexpression of Mcl-1 protected MM cells from flavopiridol-induced apoptosis. Additional analysis demonstrated that flavopiridol treatment resulted in a dose-dependent inhibition of phosphorylation of the RNA polymerase II COOH-terminal domain, thus blocking transcription elongation. These data indicate that Mcl-1 is an important target for flavopiridol-induced apoptosis of MM that occurs through inhibition of Mcl-1 mRNA transcription coupled with rapid protein degradation via the ubiquitin-proteasome pathway.


Mechanisms involved in the differential bone marrow homing of CD45 subsets in 5T murine models of myeloma
Kewal Asosingh, Eline Menu, Els Van Valckenborgh, Isabelle Vande Broek , Ivan Van Riet, Ben Van Camp, Karin Vanderkerken
Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
Clinical and Experimental Metastasis
19 (7): 583-591, 2002

Abstract

Multiple myeloma (MM) is an incurable plasma cell cancer, localized in the bone marrow (BM). The mechanisms used by these cells to (re-)enter this organ remain largely unknown. Recently, we reported that both CD45+ and CD45- myeloma cells home to the BM and induce myeloma disease. In this work, we investigated the underlying mechanisms involved in the homing of CD45+ and CD45- myeloma cells in the experimental 5T2MM and 5T33MM murine models. In vivo tracing of flow cytometric sorted and radioactively labeled CD45 subsets revealed a reduced homing of the CD45- 5TMM cells to the BM as compared to the CD45+ 5TMM cells. Migration assays demonstrated an impaired chemotaxis towards BM endothelial cell conditioned medium, BM stromal cell conditioned medium and towards the basement membrane component laminin-1 of the CD45- 5TMM cells compared to the CD45+ subset. Matrix metalloproteinase-9 (MMP-9) and urokinase type plasminogen activator (uPA) are key extracellular matrix proteases involved in the invasion of cancer cells. Inhibitor and antibody blocking experiments demonstrated the involvement of both in the invasion of the 5TMM cells. CD45- 5TMM cells had a low secretion of MMP-9 and (for the non-aggressive line 5T2MM only) a low cell surface expression of uPA receptor, as revealed by gelatin zymography and flow cytometric analysis, respectively. Accordingly, the synthetic basement membrane invasive capacity of the CD45- 5TMM subpopulations was also impaired. Our results indicate that CD45+ and CD45- 5T myeloma cells have a differential BM homing attributable to differential migratory and invasive capacities.


RANK ligand and osteoprotegerin in myeloma bone disease.
Sezer O, Heider U, Zavrski I, Kuehne CA, Hofbauer LC.
Blood 2002 Nov 7; [epub ahead of print]

Myeloma bone disease is due to interactions of myeloma cells with the bone marrow microenvironment, and is associated with pathological fractures, neurological symptoms and hypercalcemia. Adjacent to myeloma cells, the formation and activation of osteoclasts is increased which results in enhanced bone resorption. The recent characterization of the essential cytokine of osteoclast cell biology, receptor activator of NF-kappaB ligand (RANKL) and its antagonist osteoprotegerin (OPG), have led to a detailed molecular and cellular understanding of myeloma bone disease. Myeloma cells induce RANKL expression in bone marrow stromal cells, and direct RANKL expression by myeloma cells may contribute to enhanced osteoclastogenesis in the bone microenvironment in myeloma bone disease. Furthermore, myeloma cells inhibit production and induce degradation of OPG. These effects result in an increased RANKL-to-OPG ratio which favours the formation and activation of osteoclasts. Patients with myeloma bone disease have inappropriately low serum and bone marrow levels of OPG. Specific blockade of RANKL prevented the skeletal complications in various animal models of myeloma, and suppressed bone resorption in a preliminary study of patients with myeloma bone disease.


Are Monoclonal Gammopathies in Rheumatoid Arthritis Predictive for Lymphoproliferative Disorders?
Luis A. Toro-Jiménez; William Cáceres; Edwin Mejías
JCR: Journal of Clinical Rheumatology 2002; 8(5):243-246

There is limited evidence for the association of specific malignancies with rheumatoid arthritis (RA). Monoclonal gammopathies can occur in RA. Their predictive value for the development of a lymphoproliferative disorder remains unclear and disputed. We reviewed charts of 214 RA patients all of whom had at least one serum protein electrophoresis. We performed a retrospective study of 12 patients with RA and an M spike. We further characterized the M spike by serum immunofixation and bone marrow studies. The median age at which the M spike was identified was 69 years. IgG was the predominant gammopathy in 50% of patients, with no difference in the amount of kappa ([kappa]) and lambda ([lambda]) chains.

One patient was diagnosed with multiple myeloma, one with an undefined primary lymphoproliferative disorder, one with T-cell leukemia, five with myelodysplastic syndrome, and four with monoclonal gammopathy of undetermined significance at most recent evaluation. Of our patients, 42% had a myelodysplastic syndrome, which has not been previously reported, and, in contrast to previous reports, no lymphomas were identified. The follow-up evaluation of patients with myelodysplastic syndrome and monoclonal gammopathy of undetermined significance is important because they may progress to an overt neoplasia.


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