Dissertation
Dissertation > Medicine, health > Oncology > Hematopoietic and lymphoid neoplasms

Study on the Reversal Effect of Cyclosporin A in Multidrug Resistance with Leukemia and Multiple Myeloma Patients

Author LiGuangYao
Tutor WangChunBo;YangChunZheng
School Qingdao University
Course Pharmacology
Keywords multidrug resistance cyclosporin A resistance-reversal agent Sorcin gene mdr1
CLC R733
Type Master's thesis
Year 2002
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Objective Expression and clinical implication of soluble resistance-associated calcium-binding protein(sorcin)gene and multidrug resistance gene(mdrl)and p-glycoprotein (Pgp) in leukemia and multiple myeloma patients. To study reversal effect and molecular machine-made and standard dosage of cyclosporin A(CsA) in multidrug resistance with leukemia and multiple myeloma patients.Methods A semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) ,northern blot,cDNA microarray.immunocytochemistry and fluorescence activated cell screening(FACS)was used to investigate and compare transcription levels of the human sorcin and mdrl/Pgp gene in cell lines of K562/A02 and 158 samples from patients with AL and CML and MM and normal controls and and 27 samples from control group. They were used to detect and appraise the reversal effects of CsA in 18 cases of AL,9 cases of CML,8 cases of MM with clinical drug resistance and cell lines of K562/A02. To study the relationship between the sorcin gene and mdrl/Pgp gene and their significance in clinical drug resistance and the prognosis in the patients,Results In vitro,CsA synergistically potentate the cytotoxicity of DNR to the Pgp-overexpressing K562/A02 cells. CsA increased the intracellular accumulation of DNR and inhibited the P-glycoprotein pump-efflux activity in a time-related manner. Moreover, it did not reduce the expression of the sorcin and mdrl genes in K562/A02 cell as e-valuated by RT-PCR assay. Sorcin and mdrl gene expression was significantly greater in samples from patients with AL and CML and MM compared with samples from normal peripheral mononuclear cell and patients with non-leukemia(P<0. 001). While sorcin gene expression was found to be higher in relapsed/refractory patients than those at presentation and completed remission in acute myeloid leukemia(AML) (P<0. 01, P< 0. 05). Sorcin gene overexpress was significantly lower in clinical non-resistant patients than in clinical resistant samples(P<0. 001). CR percentages of these two groups were 20.0% and 80. 0%, respectively. Patients with sorcin overexpression had a lower CR than those who had not in untreated samples(P<0. 001), the higher the expression of sorcin is, the lower the CR rate resulted in. Sorcin gene positive expression was higherin samples from patients with M5 than in samples from M2,M3,M4 in AML and so on . The amplification of sorcin gene and mdrl gene in AML were significantly higher than that in normal control, and the amplification of sorcin gene related to the amplification of mdrl gene(P<0. 001); the co-amplification of sorcin and mdrl related to the clinical drug resistance and the prognosis in AML too. Sorcin+/mdrl+ overexpress was significantly lower in clinical non-resistant patients compared to clinical resistant samples (P< 0. 001). CR percentage were displayed in 7. 1% and 91. 4% of patients, respectively patients with sorcin+/mdr-f- overexpress had a lower CR than those who had not in untreated samples(P<0. 001). Sorcin gene expression was found to be higher in blast cri-sis(BC) patients than those at chronic phase(CP) and accelerating phase(AP) in patients with CML. Sorcin gene overexpress was significantly lower in CP patients than in BC samples(P = 0. 0314) ; there was no difference between the sorcin gene overexpress of the BC and AP cases(P = 0. 183). There was difference about the mdrl/Pgp positive express in CML case. Mdrl gene overexpress was significantly higher in BC patients than those at CP and AP in patients with CML(P = 0. 002, P = 0. 024). Pgp overexpression was found to be higher in BC patients than those at CP and AP in patients with CML; Pgp gene overexpress was significantly higher in BC patients than those at CP in patients with CML (P = 0. 016). Sorcin gene expression was found to be higher in relapsed/refractory patients than those at presentation and completed remission in MM. Sorcin gene overexpress was significantly lower in clinical non-resistant patients than in clinical resistant samples(P=0. 004). CR percentages of these t

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