title: In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia.
abstract: Cellular drug resistance is thought to be an important cause of the poor prognosis for children with relapsed or refractory acute lymphoblastic leukemia (ALL), but it is unknown when, to which drugs, and to what extent resistance is present. We determined in vitro resistance to 13 drugs with the MTT assay. Compared with 141 children with initial ALL, cells from 137 children with relapsed ALL were significantly more resistant to glucocorticoids, L-asparaginase, anthracyclines, and thiopurines, but not to vinca-alkaloids, cytarabine, ifosfamide, and epipodophyllotoxins. Relapsed ALL cells expressed the highest level of resistance to glucocorticoids, with a median level 357- and >24-fold more resistant to prednisolone and dexamethasone, respectively, than initial ALL cells, whereas the resistance ratios for the other drugs differed from 0.8- to 1.9-fold, intraindividual comparisons between initial and relapsed samples from 16 children with ALL showed that both de novo and acquired drug resistance were involved. Specific in vitro drug-resistance profiles were associated with high-risk relapsed ALL groups. In vitro drug resistance was also related to the clinical response to chemotherapy in relapsed/refractory childhood ALL. We conclude that drug resistance may explain the poor prognosis for children with relapsed/refractory ALL. These day may be helpful to design alternative treatment regimens for relapsed childhood ALL.
authors.affiliation: Department of Pediatrics, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Klumper
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: A J
authors.initials: AJ
authors.lastname: Veerman
authors.forename: D R
authors.initials: DR
authors.lastname: Huismans
authors.forename: A H
authors.initials: AH
authors.lastname: Loonen
authors.forename: K
authors.initials: K
authors.lastname: Hählen
authors.forename: G J
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: E R
authors.initials: ER
authors.lastname: van Wering
authors.forename: R
authors.initials: R
authors.lastname: Hartmann
authors.forename: G
authors.initials: G
authors.lastname: Henze
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001215:Asparaginase / Q000494:pharmacology; D002648:Child; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology / Q000627:therapeutic use; D007069:Ifosfamide / Q000494:pharmacology; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016879:Salvage Therapy
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D005938:Glucocorticoids; D001215:Asparaginase; D007069:Ifosfamide; D015255:Idarubicin