Studies of P-glycoprotein in chronic myelogenous leukaemia patients: expression, activity and correlations with CD34 antigen.

Over-expression of the P-glycoprotein (Pgp), transmembrane drug efflux pump, has been shown to cause multidrug resistance of tumour cells (MDR). To investigate the clinical significance of Pgp expression for chronic myeloid leukaemia (CML) diagnosis and monitoring we have studied 38 CML patients in various phases of the disease (chronic phase, CP; accelerated phase, AP; blast crisis, BC). Anti-Pgp monoclonal antibody UIC2 and FACScan analysis were used. Pgp functional activity was investigated by evaluation of verapamil influence upon rhodamine 123 efflux from the cells. Correlations between Pgp and CD34 expression were investigated. In CP, Pgp-expressing cells were found in 2/14 patients; in one of them Pgp proved to be non-functional. There were few Pgp-expressing cells in AP cases. The group of BC patients consisted of cases resistant to chemotherapy. This gave us the opportunity to consider whether drug resistance of BC CML patients is preferentially connected with Pgp-mediated MDR. 11/22 BC patients had 20% or more of Pgp-expressing blasts in the peripheral blood. In all four Pgp+ BC cases studied for Pgp activity this protein was functional. Only 4/22 BC patients demonstrated large (40% or more) fractions of Pgp+ blasts. Moreover, sequential studies of 11 BC CML patients during treatment revealed an increase in the number of Pgp-expressing cells in only two cases. This suggests that Pgp+ cells did not often accumulate in BC CML patients due to chemotherapy and are the cause of drug resistance in only a few cases. A positive correlation between Pgp and CD34 expression was found (r = 0.69; P = 0.0004). 3/22 BC CML patients had large fractions of both Pgp+ and CD34+ blasts in their peripheral blood. The BC CML patients with this immunophenotype of blast cells may represent a subtype of BC CML resistant to treatment due to Pgp overexpression.

[The clinical significance of the expression of the multiple-drug resistance protein P-glycoprotein in chronic myeloleukemia]. / Klinicheskoe znachenie ékspressii belka mnozhestvennoi lekarstvennoi ustoichivosti P-glikoproteina pri khronicheskom mieloleikoze.

Cell resistance to pharmaceutical agents arises among other causes because of multiple drug resistance induced by P-glycoprotein (P-gp). The analysis of expression of P-gp and differentiation antigens of hemopoietic cells has been made on myeloid cells from 14 patients in CML chronic phase and 25 with CML acceleration and in blast crisis. Surface antigen expression was evaluated at flow cytofluorimetry (FACScan unit). Fluorescent dye rodomin (Rh123) helped examine P-gp functional activity. A close relationship is shown between P-gp expression and CD34 (r = 0.69. p = 0.0004), this giving evidence of these antigens expression on the same cells. In chronic phase P-gp is expressed on a few cells in some patients, its activity being low or absent. The appearance of UIC-2+ cells was unrelated to previous chemotherapy and brought no resistance to treatment. In terminal stage P-gp is expressed in 50% of cases. Functional tests identified the active protein in blast populations with a large number of UIC-2+ cells and in some patients with a small number of cells expressing P-gp. Therefore, comprehensive clinical investigations are needed of multiple drug resistance, though in half of the resistant patients in AML blast crisis P-gp+ cells were not identified suggesting the existence of other mechanisms responsible for resistance to treatment.