P-glycoprotein, lung resistance-related protein and multidrug resistance-associated protein in de novo adult acute lymphoblastic leukaemia Daniela Damiani, 1 Angela Michelutti, 1 Mariagrazia Michieli, 2 Paola Masolini, 1 Raffaella Stocchi, 1 Antonella Geromin, 1 Anna Ermacora, 1 Domenico Russo, 1 Renato Fanin 1 and Michele Baccarani 3 1 Division of Haematology, Department of Medical and Morphological Research, University Hospital, Udine, 2 Medical Oncology B, Centro di Riferimento Oncologico, National Cancer Institute, IRCCS, Aviano, and 3 Institute of Haematology and Medical Oncology ÔL and A. Sera `gnoliÕ, University of Bologna, Bologna, Italy Received 31 July 2001; accepted for publication 3 October 2001 Summary. P-glycoprotein (P-gp), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression, and blast cell intracellular daunorubicin accumulation (IDA) were evaluated in 95 previously untreated cases of adult acute lymphoblastic leukaemia (ALL) using flow cytometry. Forty-five out of 95 (47%) patients were P-gp positive (+), 12/66 (18%) were LRP+ and 11/66 (17%) were MRP+. Eighteen out of 66 (28%) patients showed a simultaneous multidrug resistance (MDR)-related protein expression higher than controls for more than one protein, while 24/66 (36%) cases did not overexpress any protein. Twenty-one out of 24 (87%) cases overexpressing at least one MDR-related protein had a defect in accumulating daunorubicin into their blast cells, while only 4/24 (16%) cases who did not overexpress any protein had similar fea- tures. The complete remission rates were similar in MDR- positive and -negative (–) patients but relapses within 6 months were more frequent in P-gp+ cases, and therefore the disease-free survival duration was shorter in P-gp+ than in P-gp– patients (P ¼ 0Æ01). The number of MRP+ and/or LRP+ cases was too small to be able to draw any conclusion on their role in affecting or predicting therapy outcome. In conclusion, P-gp overexpression associated with a defect in daunorubicin accumulation is a frequent feature in adult ALL at onset and seems to be related to poorer therapy outcome and, consequently, a shorter disease-free survival. LRP and MRP overexpression seems to be a rare event and no conclusion can be drawn on its prognostic role. Keywords: P-glycoprotein, multidrug resistance-associated protein, lung resistance-related protein, adult acute lymphoblastic leukaemia. Intensive treatment with anticancer agents and well- designed chemotherapeutic strategies significantly improve outcome in childhood acute lymphoblastic leukaemia (ALL), and long-term disease free survival is obtained in 70% of cases. In contrast, adults with ALL have lower complete remission (CR) rates and substantially poorer rates of long- term survival despite the application of therapeutic strate- gies that are successfully used in children (Copelan & McGuire, 1995). To explain the differing prognoses, and the poorer outcome in older patients, many factors must be taken into consideration: differences in disease biology, including a higher incidence of chromosome translocations associated with poor prognosis, in particular the Philadelphia chro- mosome (Copelan & McGuire, 1995), differences in drug metabolism, especially regarding methotrexate (Goker et al, 1993; Copelan & McGuire, 1995), a greater haematological and extrahaematological toxicity in older patients (Hoelzer, 1993). More recently, another potential factor causing poor adult response to chemotherapy has been related to the presence of the multidrug resistance (MDR) phenomenon (Endicott & Ling, 1989; Goasguen et al, 1993; List, 1993). Classic MDR is due to the expression of P-glycoprotein (P-gp), a protein encoded by the mdr-1 gene, which belongs to the ATP-binding cassette of the transporter gene super- family. This gene maps on the long arm of chromosome 7 and its product, P-gp, acts as an energy–dependent trans- membrane pump that actively effluxes drugs and dyes Correspondence: Dr Daniela Damiani, Division of Haematology, University Hospital, P.le S. Maria della Misericordia, 33100 Udine, Italy. E-mail: Ematologia@drmm.uniud.it British Journal of Haematology, 2002, 116, 519–527 Ó 2002 Blackwell Science Ltd 519