| Myelodysplastic syndrome(MDS)is a malignant and clonal disease originated from pluripotential hemopoietic stem cells which can be induced by many factors. For many years, effective therapeutic measure for MDS was deficient. Although some recent reports reported that the traditional Chinese medicine pills of compound melanteritum had better effects on MDS,it had quite little effect on refractory anemia with excess of blasts(RAEB)and refractory anemia with excess of blasts-transformant(RAEB-T). For the past few years,the close relation between the generation ,development ,prognosis of malignant disease of hematological system and neogenesis of blood vessel was one of hot spots which people pay attention to. Thalidomide,which was banned once for the teratogenic effect,had the inhibitory action on vascularization,etc. It now has been used for the therapy of many malignant blood disease,especially for the refractory multiple myeloma(MM). Thalidomide is glutamic acid derivative,which chemname is N-(2,6-dioxy-3-piperidyl)-phthalimide or 2-(2,6-dioxy-3-piperidyl)-1H-isoindole-1,3-(2H)-diketone. It is white crystalline powder,odorless,tasteless,slightly soluble in water ,methanol,ethanol or acetone,easily solube in dimethylformamide or pyridinium,non-soluble in ethylether,chloroform or benzene . Its melting point is 269℃～274℃,half life is 6 hours,and metabolism by liver pass is hardly. Antineoplastic action mechanism of thalidomide has not been clear now,but correlated experiments cued that it may be related with anti-tumor vascularization,inhibition role of the TNF-αsynthesis,immunomodulation,promotion to apoptosis and enhance role of the chemotherapy effect,accommodation of adhesion molecule expression. 1.Anti-tumor vascularization Although the mechanism of action was not clear,it is the most confessed and joyful findings at present time , and some experiments had had positive results on it. In 1999,Verheul etc. reported that combination of thalidomide and sulindac had better effect (65% and 74%)than single use on inhibitory action of therabbit cornea vascularization which induced by basic fibroblast growth factor(bFGF) and vascular endothelial growth factor(VEGF). Liu etc. found that blood vessel endothelium can secrete caveolin-1 , it has down-regulation role on VEGF-R signal conduction in vivo,so bring into the inhibition role of VEGF promotion vascularization,but high concentration of VEGF,bFGF,hepatocyte growth factor etc. can inhibit the expression of caveolin-1,this may be an important path of endotheliocyte proliferation. Liu used high concentration of above factors on homo-umbilical core endothelial cell ECV304 , found that caveolin-1 level decreased. But the factors may inhibit endothelio proliferation by prevention of down-regulation which induced by VEGF if thalidomide was added. 2.Inhibition role of the TNF-αsynthesis The growth of myeloma cell relies on IL-6 autocrine and paracrine secretion,but many kinds of tumour cells and cell lines,A549 lung cancer cells,724 carcinoma of bladder cells,cervical cancer cells etc.,can express IL-6 mRNA and secrete IL-6. High TNF-αcan stimulate macrophagocyte,neutrophile granulocyte,Tcell and vascular endothelial cell to secrete IL-1,IL-6,IL-8. Correlated research found that IL-6 and TNF-αactivity in ascites and serum of enteron tumor patients increased significantly. Thalidomide can degradate TNF-αmRNA to inhibit the synthesis of TNF-αand decrease the generation of IL-6,so play the inhibition role on the tumorous growth. 3.Immunomodulation A great deal of evidence showed that thalidomide did not inhibit lymphocyte proliferation directly,it was by the paths below approximately:Inhibit the chematropism of infl. Leucocyte;Accommodate white cell adhesion molecule mediated by TNF-α;Degrade phagocytosis of polymorphonuclear leucocytes;Increase Monocyte to generate IL-4,inhibit γ-INF generation,and it may induce the apoptosis of Th cells. 4. Promotion to apoptosis and enhance role of the chemotherapy effect Two kinds of thalidomide analogue were found now,one kind is phosphodiesterase-4 inhibitor called elective cell factor inhibitor,can inhibit TNF-α,but can not activate T cells effect. Theother is non-phosphodiesterase inhibitor called immunomodulator( IMiDs ) , can activate T cells and promote T cells to secreteγ-TNF and IL-2. Hideshima etc. found IMiDs can induce apoptosis of multiple myeloma cells(MM)which were drug resistant for Phenylalanine ,adriamycin ,dexamethasone and neoplastic cells of MM patients,or make G1 stage growth retardation. Thalidomide and IMiDs can increase antitumor activity of hexadecadrol which was inhibited by IL-6. 5.Accommodation of adhesion molecule expression The effect of thalidomide on adhesion molecule was as follows : Thalidomide may accommodate the expression of ICAM-1(CD54),VCAM-1(CD106),E selectin and L selectin in vascular endothelial cell,lymphocyte,monocaryotic cell and tumour cell surface. These adhesion molecules have close relation on neovascularization ,invasion and transfer. One of the thalidomide antineoplastic mechanisms was the accommodation of adhesion molecule expression. In this study, we investigated twenty-seven patients with MDS. The patients were randomly divided into treatment group, 14... |
