Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Determining in vitro drug resistance may reveal clinically relevant information in childhood leukemia. Using the methyl-thiazol-tetrazolium assay, the resistance of untreated leukemic cells to 21 drugs was compared in 128 children with acute myeloid leukemia (AML) and 536 children with acute lymphoblastic leukemia (ALL). The differences between 3 French-American-British (FAB) types (M1/M2, M4, and M5) were also compared. AML was significantly more resistant than ALL to the following drugs, as noted by the median resistance: glucocorticoids (greater than 85-fold), vincristine (4.4-fold), L-asparaginase (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 median LC50 values (the drug concentration that kills 5% of the cells) were equal. Also, busulfan, amsacrine, teniposide, and vindesine showed no significant 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 to most drugs frequently used in AML, as indicated by the following ratios of median sensitivities: the anthracyclines (2.6- to 3.2-fold), mitoxantrone (12.5-fold), etoposide (8.7-fold), and cytarabine (2.9-fold). For etoposide and cytarabine (5.4- and 3.4-fold, respectively) FAB M5 was also significantly more sensitive than FAB M1/M2. FAB M5 was equally sensitive to L-asparaginase and vincristine as ALL. Only 15% of the AML samples were "intermediately" sensitive to glucocorticoids, mainly in FAB M1/M2. The poorer prognosis of childhood AML is related to resistance to a large number of drugs. Within AML, FAB M5 had a distinct resistance pattern. These resistance profiles may be helpful in the rational design of further treatment protocols. (Blood. 2000;96:2879-2886)
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PMID:Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia. 1102 25

To determine the clinical relevance of in vitro drug chemoresistance in childhood acute myeloid leukemia, we used an MTT assay to test leukemic cells from 132 newly diagnosed children. Patients were diagnosed according to the French-American-British (FAB) classification as follows: M0 (n = 12), M1 (n = 16), M2 (n = 53), M4 (n = 17), M5 (n = 19) and M7 (n = 15). The results revealed that, compared to leukemic cells from complete-responders (n = 107), those from non-responders who failed induction therapy (n = 17) were 1.4 to 5.0 times more resistant in vitro to cytarabine (P = 0.005), melphalan (P = 0.003), etoposide (P = 0.011), L-asparaginase (P = 0.017), aclarubicin (P = 0.026) and dexamethasone (P = 0.039). For seven other drugs tested, the median lethal dose of 70% and leukemic cell survival of non-responders were higher than those of complete-responders, but the difference was not statistically significant. We sought correlations between FAB subtypes and in vitro drug resistance. Leukemias of the FAB M4 and M5 subtype were more sensitive to L-asparaginase (P = 0.01, P = 0.0036) than those of the FAB M2 subtype. FAB M5 leukemia was more sensitive to etoposide than were the FAB M2, M4 and M7 subtypes (P = 0.001, P = 0.034, P = 0.023, respectively). By contrast, FAB M5 leukemia was significantly more resistant to prednisolone and dexamethasone than were the FAB M0, M1, M2, M4 and M7 subtypes. We sought correlations between in vitro drug resistance and long-term clinical outcome, but found no associations in this case. These results suggest that in vitro resistance to cytarabine, melphalan, etoposide, L-asparaginase, aclarubicin and dexamethasone might represent factors that can predict response to the early course of therapy. Selecting an appropriate anti-cancer drug according to the FAB classification together with drug sensitivity testing may contribute to improved prognoses in childhood acute myeloid leukemia.
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PMID:Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia. 1175 10