Clinical And Experimental Studies On The Reversal Of Multidrug Resistance By Cyclosporine A

Multidrug resistance (MDR) is the main problem of successful chemotherapy for leukemia.Study on its mechanism and reversion is the hot spot for the chemotherapy of leukemia. The overexpression of MDR1 gene(mdr1) and a 170KD glycoprotein (P₁₇₀) encoded by mdi1 gene is the main mechanism of MDR. Various MDR reversal agents have been investigated recently, among them. Cyclosporine A(CsA) is the most prospective agent in clinical reversal of MDR. This paper presents the results of clinical reversal of MDR by CsA and its mechanism on human acute leukemia cells as well as MDR human leukemia cell line-K₅₆₂/AO₂ cells.MDR has been successfully reversed by CsA with the elimination of MDR acute myeloid leukemia (AMD cells in a patient with refractory AML:M_4b which had no response to two courses of full dosage conventional chemotherapy regimen. CsA could increase intracellular concentration of daunorubicin (DNR) in patient's leukemia cells. The effects of CsA on promoting influx and inhibiting efflux of DNR were observed in K₅₆₂/AO2 cell. The sensitivity of K₅₆₂ /A02 cell to DNR increased by 3.2 folds. Priliminary result also indicates that mdr1 expression might be down- regulated by CsA by retrotranscriptase/polymerase chain reaction technique.Previous studies indicated that enhanced activity of protein kinase C(PKC) may play a role in MDR in some ceil lines. A comparison of PKC activity between K₅₆₂/A02 and its wild type cell line-K₅₀₂ reveals that PKC activity in cell membrane of...