The influence of thalidomide therapy on cytokine secretion, immunophenotype, BCL-2 expression and microvessel density in patients with resistant or relapsed multiple myeloma.
Thalidomide (THAL) is currently used as a novel drug in patients with chemotherapy resistant or relapsed multiple myeloma. THAL antitumor activity seems to be very complex, however the precise mechanisms of its action are still not fully understood. The aim of this study was to assess some of possible mechanisms of THAL action both in in vivo analysis of immune cells phenotype and in in vitro cultures with THAL. The study involved 30 patients with relapsed or chemotherapy refractory multiple myeloma who were qualified to THAL treatment. We assessed immunophenotype of malignant plasma cells and T lymphocytes in both peripheral blood (PB) and bone marrow (BM) samples taken before and after 4 and 8 weeks of THAL treatment. Before therapy cytokine secretion (VEGF, HGF, bFGF, TNF, IL-6 an sIL-6R) and Bcl-2 expression in PB and BM cell cultures with THAL were analyzed. We used flow cytometry technique and ELISA method. The clinical response to therapy was assessed after 4 and 8 weeks of treatment. We also investigated microvessel density (MVD) in bone marrow samples before the THAL treatment and after 6 months of therapy in the group of responding patients. In cell cultures with THAL we detected statistically significant lowering of analyzed cytokines concentration and the decrease in Bcl-2 expression by malignant plasma cells in BM and CD8(+) T lymphocytes in BM and PB. In the group of patients responding to therapy we observed the decrease in the number of myeloma cells and significant increase of CD4(+) and CD8(+) cells in both PB and BM samples. There was statistically significant increase of CD3(+)/CD69(+) cells in the course of therapy, while the percentage of CD3+/HLA-DR(+) cells was significantly lower after 8 weeks of therapy. We also detected lowering of MVD after THAL therapy in responders group. The obtained results demonstrate that THAL efficacy in MM is multidirected and included such mechanisms like down-regulation of proangiogenic cytokines, that could lead to lowering of MVD, induction of apoptosis and influence on malignant cells and T lymphocytes immunophenotype.
Dmoszynska
A
A
Department of Hematology, Medical University of Lublin, 20-950 Lublin, Poland. mpodhor@poczta.onet.pl
Podhorecka
M
M
Manko
J
J
Bojarska-Junak
A
A
Rolinski
J
J
Skomra
D
D
D000284:Administration, Oral; D018414:CD8-Positive T-Lymphocytes; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D013792:Thalidomide / Q000494:pharmacology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013792:Thalidomide