Changing picture of cellular drug resistance in human leukemia.
A relatively well documented and seemingly firm overall picture of mechanisms involved in leukemia-cell drug resistance has evolved since the 1970s, where mechanisms involved in multidrug resistance towards anti-leukemia chemotherapeutic compounds were first described. At that time, based on available data, resistance associated with overexpression of the cell-surface transmembrane ATPase P-glycoprotein (P-170, P-gp, the product of the MDR1 gene) was described as "the" cause of multidrug resistance in cancer cells. However, during the 1980s and later on other mechanisms were described as candidate causes of multidrug resistance in human leukemia. Moreover, research of the past decade has provided us with an enormous increase in the amount of data and knowledge on the cell-biological and--to an even higher extent--the molecular-genetic processes governing cell survival and death in cancer cells. This, in turn, has improved the possibilities of designing and developing better drugs and drug combinations in leukemia. Along this line, based on rational drug design, imatinib, a 2-phenylaminopyrimidine derivative, has very recently been introduced and found to be an efficient inhibitor of the altered tyrosine kinase, which arises as a product of the BCR-ABL fusion transcript in Philadelphia chromosome positive (Ph+) cases of CML. This new compound appears to be the first of a (hopefully) large family of small organic molecules with a more specific inhibiting activity against the pathogenetic defects in leukemia as well as cancer. With this novel compound, as with all other known individual drugs and classes of chemotherapeutic drugs, drug resistance is seen. To what extent drug resistance towards this novel compound (and its successors) will follow patterns of drug resistance that are already known or entirely new mechanisms of drug resistance is yet to be seen.
Nørgaard
Jan Maxwell
JM
Department of Hematology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. janmaxgaard@dadlnet.dk
Olesen
Lene Hyldahl
LH
Hokland
Peter
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1