Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia

Determining in vitro drug resistance may reveal clinically relevant informa tion in childhood leukemia. Using the methyl-thiazol-tetrazolium assay, the resistance of untreated leukemic cells to 21 drugs was compared in 128 chi ldren with acute myeloid leukemia (AML) and 536 children with acute lymphob lastic leukemia (ALL), The differences between 3 French-American-British (F AB) types (M1/M2, M4, and M5) were also compared. AML was significantly mor e resistant than ALL to the following drugs, as noted by the median resista nce: glucocorticoids(greater than 85-fold), vincristine(4.4-fold),L-asparag inase (6.9-fold), anthracyclines(1.8- to 3.4-fold), mitoxantrone (2.6-fold) , etoposide (4.9-fold), platinum analogues (2.4- to 3.4-fold), ifosfamide ( 3.5-fold), and thiotepa (3.9-fold). For cytarabine and thiopurines, the med ian LC50 values (the drug concentration that kills 5% of the cells) were eq ual. Also, busulfan, amsacrine, teniposide, and vindesine showed no signifi cant differences, but the numbers were smaller, and the median LC50 values were 1.3- to 5.2-fold higher in AML. None of the drugs demonstrated greater cytotoxicity in AML, FAB M5 was significantly more sensitive than FAB M4 t o most drugs frequently used in AML, as indicated by the following ratios o f median sensitivities: the anthracyclines (2.6- to 3.2-fold), mitoxantrone (12.5-fold), etoposide (8.7-fold), and cytarabine (2.9-fold). For etoposid e and cytarabine (5.4- and 3.4-fold, respectively) FAB M5 was also signific antly more sensitive than FAB M1/M2. FAB M5 was equally sensitive to L-aspa raginase and vincristine as ALL. Only 15% of the AML samples were "intermed iately" sensitive to glucocorticoids, mainly in FAB M1/M2. The poorer progn osis of childhood AML is related to resistance to a large number of drugs. Within AML, FAB M5 had a distinct resistance pattern. These resistance prof iles may be helpful in the rational design of further treatment protocols.( Blood. 2000;96:2879-2886) (C) 2000 by The American Society of Hematology.