Chemo- and radiation sensitivity of xenografted acute lymphoblastic leukemias--correlation to the expression of multidrug resistance proteins.
The aim of our study was to characterise, for the first time, the chemo- and radiation sensitivity of seven pediatric acute lymphoblastic leukemias xenotransplanted into immunodeficient NOD/SCID mice and to correlate the findings with the expression of three drug resistance proteins, P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP1) and lung resistance protein (LRP). Mice were treated with single drugs used in clinical protocols: daunorubicin, doxorubicin, cyclophosphamide, vincristine, cytarabine, asparaginase and methotrexate. Two ALL samples, established from primarily diagnosed patients, responded to 5 or 6 of the tested cytostatics, respectively, while 3 out of 5 ALLs from relapse patients were only sensitive towards 2-4 drugs tested. Daunorubicin was more efficient than doxorubicin. The response of xenografted ALL toward vincristine and cyclophosphamide was inversely correlated with the expression of P-gp, LRP and MRP1 (R2 = 0.71, 0.70 and 0.64 for vincristine and 0.44, 0.70 and 0.60 for cyclophosphamide). A good correlation could be detected between the expression of P-gp and LRP (R2 = 0.88), P-gp and MRP1 (R2 = 0.75) and LRP and MRP1 (R2 = 0.90). The highest co-expression of the drug resistance proteins in the leukemia ALL-SCID 6 coincided with a high resistance to radiation and chemotherapy. Prediction of the individual drug resistance profile of a patient on the basis of results from the ALL-SCID xenograft studies was not possible because of the relatively long time necessary and because of the changes in the expression of P-gp, LRP and MRP1 during the murine generations. We conclude that in the drug resistance phenotype of ALL not only the above mentioned proteins but a variety of different molecules are involved.
Fichtner
Iduna
I
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin-Buch, Germany. Fichtner@mdc-berlin.de
Paal
Krisztina
K
Borgmann
Anja
A
Badiali
Lucia
L
Wurm
Reinhard
R
Henze
Günter
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000293:Adolescent; D000818:Animals; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy / Q000628:therapy*; D011836:Radiation Tolerance / Q000502:physiology*; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein