| Multiple myeloma (MM) is a systemic malignancy of plasmacells, characterized by secretion of monoclonalimmunoglobulin and osteolytic lesions. MM is a commonhematological tumor and accounts for approximately 10percent of hematological malignancies. Survival time hasbeen improved from a median of 7 months in the 1950s to over30 months in recent years because of progress in chemotherapy.However, MM still remains an incurable disease. Despiteindubitable advances in treatment and prolongation ofsurvival time of patients treated with high-dosechemotherapy followed by peripheral autologous stem cellstransplantation, only a few patients achieve long-termremission or are cured, due to the high cost oftransplantation, the refractory to chemotherapy and so on.Therefore, the new therapeutic strategy targeting therelapsed or resistant MM patients has been encouraged to bedeveloped.Thalidomide, known as a sedative drug, was introduced forthe treatment of morning sickness in pregnant woman but waswithdrawn from clinical use in 1962 due to its severeteratogenic effect on the fetus. It was established thatthis complication was secondary to inhibition of bloodvessel growth in the development of fetal limb buds. Moreover,thalidomide was found to have immunomodulatory properties,i.e. regulating secretion of many cytokines, such as tumornecrosis factor (TNF). Research on pathological mechanism of MM in early 1990sfound that microvascular density (MVC) in bone marrow ofpatients with MM increased. MM cells adhering to bone marrowstem cells (BMSCs) can upregulate BMSCs and MM cellssecretion of VEGF and bFGF, both of which promoteproliferation and migration of endothelial cells andangiogenesis, resulting in increasing of MVD. The newbornblood vessels not only provide nutrients for tumor cells,but also introduce a new pathway for tumor metastasis.Research has shown that thalidomide suppresses secretion ofVEGF and bFGF, leading to inhibition of newborn vessels. The anti-tumor mechanism of thalidomide is rathercomplicated. Inhibition of newborn blood vessels is not itsonly pathway to treat MM. Thalidomide can also induce MMcells'apoptosis and G1 phase growth retardation to inhibitproliferation of MM cells and BMSCs directly throughfree-oxygen-radical-induced DNA oxidation damage. Myelomacells can auto-secrete and para-secrete IL-6, which is themain cytokine promoting MM cells'growth. Suppressingsecretion of IL-6 by MM cells and BMSCs, thalidomide inhibitsgrowth and proliferation of MM cells indirectly. Mainlysecreted by monocytes and macrophages, and partlyauto-secreted by MM cells, TNF-αis also one of the importantcytokines participating in MM cell growth. The main functionof TNF-αis to induce low-level proliferation of MM cells,to upregulate secretion of IL-6 by BMSCs significantly, toupregulate expression of adhesive molecules (VLA-4, LFA-1)and corresponding receptors (VCAM-1, ICAM-1) in MM cells,and to promote adhesion of MM cells with BMSCs, increasingsecretion of many cytokines. Suppressing expression of TNF-αmRNA, thalidomide decreases secretion of TNF-αso as toblock or inhibit the effect of TNF-αon myeloma cells. Inaddition, in vitro experiments has shown that thalidomidecan stimulate T cells proliferation directly, increasesynthesis of IL-2 and IFN-γ, and induce the anti-tumoreffect by NK cells and LAK cells, leading to disruption ofMM cell line. Considering pharmacological action of thalidomide andincreasing MVD in MM patient, Singhal et al used singlethalidomide to treat 84 refractory or relapsed MM patientsand got remarkable therapeutic effect. From then on,researches on thalidomide or thalidomide in combination withother drugs to treat refractory or relapsed patients withMM began to practice. The effective rate of singlethalidomide treating refractory or relapsed MM is 56%,combining with dexamethasone or melphalan and prednisone (MP)can achieve 70%, combining with vincristine ,doxorubicin anddexamethasone(VAD) can get as high as 82%. These data provesthat thalidomide and thalidomide in combination with otherdrugs can treat MM effectively, Among all the regimens,combination with VAD is the most effective one. To study theclinical effect of thalidomide incorporating with VAD totreat refractory or relapsed patients with MM, 84 patientswere randomly divided into thalidomide plus VAD group andVAD group respectively. Changes of M-protein in serum,percentage of plasma cells in bone marrow, the level ofvascular endothelial growth factor (VEGF) in serum and thelevel of Hb are determined pro-and post-treatment to compareclinical effect of the two groups. All data are expressedas mean±s. Difference of the two groups and pro-andpost-treatment in the same group is expressed with the T-test.The result suggests: ①Response to thalidomide combiningwith VAD could achieve complete remission in 3patients(7.69%), partial remission in 18 patients(46.15%),minor response in 9 patients (23.08%), and no response in9 patients (23.08%). The total effective rate was76.92%(30/39), significantly higher than that in controlgroup (with total effective rate 44.44%, p=0.025). ②Aftertreatment, M-protein in serum decreased ≥50% in 19patients(48.72%) in the experiment group and 11 patients(24.44%) in the control group (p=0.021). ③The number ofmyeloma cells in bone marrow decreased > 80% in 3patients(7.69%) in thalidomide plus VAD group and 1patient(2.22%) in VAD group (p=0.043).④The level of VEGFin serum in experiment group was significantly lower thanthat in the control group(p=0.001). The level of VEGF inserum in the experiment group after 3months wassignificantly lower than pro-treatment, i.e. 416.72 ±149.81pg/ml vs. 305.61 ±114.74 pg/ml ( p=0.0032. Aftertreated for 6 months, the level of VEGF in serum was 173.18±67.15 pg/ml(p=0.0014). ⑤The level of Hb increased>20g/L in 20 patients (51.28%) in the experiment group and12 patients (26.67%) in the control group (p=0.021). The results of our study indicate that the therapeuticeffect of thalidomide combining with VAD for the refractoryand relapsed MM remarkably surpasses single VAD. After thetreatment, concentration of serum M-protein, percentage ofplasma cells in bone marrow, and the level of plasma VEGFare all obviously decreased and the concentration ofhaemoglobin is increased. The improvement of all data inexperiment group is much higher than control group.Difference of data between experiment group and controlgroup has statistic significance. The main adverse effects,which are mild, remediable and well tolerated, aredrowsiness, hypodynamia, constipation, abdominaldistension, epigastric discomfort, dry mouth, edema of lowerextremity and mild leukocyte decreasing. To sum up, treatment of thalidomide combining withVAD, which has mild adverse effect and better... |
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