Cellular drug resistance in acute myeloid leukemia: literature review and preliminary analysis of an ongoing collaborative study

Kaspers, Gertjan J. L.; Zwaan, C. Michel; Veerman, A. J. P.; Rots, Marianne G.; Pieters, R.; Bucsky, Peter; Domula, M; Göbel, U.; Graf, Norbert; Havers, W.; Jorch, Norbert; Kabisch, K; Spaar, H. J.; Ritter, J.; Creutzig, Ursula

doi:10.1055/s-2008-1043795

Cited by 27 publications

(17 citation statements)

References 18 publications

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“…They also showed that the in vitro drug resistance profiles of AML M5 samples resembled those in ALL, except that the former are resistant to glucocorticoid. 16 Similarly, we found here that M5 cells were relatively sensitive to L-ASP, and were significantly more resistant to Pred and Dex than were M0, M1, M2, M4 and M7 cells.…”

Section: Discussionsupporting

confidence: 61%

“…Klumper et al 14 suggested that in vitro resistance to AraC correlated with chemotherapy failures in 29 cases of childhood initial AML. Kaspers et al 16 reported that in a group of 55 samples of newly diagnosed children with AML patients with more than 5% blasts in their BM at day 15 of remission induction chemotherapy had AML cells that were relatively more resistant to DNR, IDA, VP16 and AraC than those of the patients with less than 5% blasts. In adult AML, several studies Correlation between drug sensitivity and FAB classification.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][10][11] There are some reports on AML using the MTT (methyl-thiazoltetrazolium) assay, [12][13][14][15][16][17] but thus far we have found only a limited number of studies on the relationship between in vitro drug resistance and clinical outcomes in childhood AML. 6,[14][15][16][17] Here, we have investigated in vitro drug resistance using the MTT assay for 132 patients with newly diagnosed AML. We show Initially, 159 patients (aged 0-16 years) with AML, diagnosed between January 1988 and February 2000, were eligible for this study.…”

Section: Introductionmentioning

confidence: 99%

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Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia

et al. 2001

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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-AmericanBritish (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 completeresponders (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. Leukemia (2001Leukemia ( ) 15, 1892Leukemia ( -1897

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia

et al. 2001

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“…Although in vitro drug resistance testing differs considerably from the in vivo situation, it does provide valuable indications as to which factors might be important in drug sensitivity in vivo (Kaspers et al, 1999). hENT1 mRNA expression correlated with sensitivity to ara-C and also seemed to correlate with sensitivity to 2-CdA, DAC and dFdC, indicating that transport across the cell membrane is an important step for deoxynucleoside analogue induced cytotoxicity.…”

Section: Discusssionmentioning

confidence: 99%

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

et al. 2005

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Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P ¼ 0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (r p ¼ À0.46; P ¼ 0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P ¼ 0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC 50 values of cladribine (r p ¼ À0.30; P ¼ 0.04), decitabine (r p ¼ À0.29; P ¼ 0.04) and gemcitabine (r p ¼ À0.33; P ¼ 0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (r p ¼ À0.31; P ¼ 0.03) and decitabine (r p ¼ 0.33; P ¼ 0.03), respectively. The dCK/PN-I ratio correlated inversely with LC 50 values for gemcitabine (r p ¼ À0.45, P ¼ 0.001) and the dCK/CDA ratio seemed to correlate with LC 50 values for decitabine (r p ¼ À0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML.

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“…We and others have already demonstrated the prognostic importance of cellular resistance in childhood leukemias. [21][22][23][24] We previously reported childhood AML to be relatively resistant to a large number of drugs when compared with childhood acute lymphoblastic leukemia (ALL). 25 Also, specific genetic ALL and AML subgroups may show different resistance profiles.…”

Section: Introductionmentioning

confidence: 99%

Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities

Zwaan

Kaspers

Pieters

et al. 2002

Blood

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Specific cytogenetic abnormalities predict prognosis in childhood acute myeloid leukemia (AML). However, it is unknown why they are predictive and whether this is related to drug resistance. We previously reported that Down syndrome (DS) AML was associated with favorable resistance profiles. Here, we successfully analyzed drug resistance and (cyto-) genetic abnormalities of 109 untreated childhood AML samples using the 4-day total cell-kill methyl-thiazol tetrazolium (MTT) assay. Patients were classified according to the genetic abnormalities in the leukemic cells: t(8;21), inv(16), t(15;17), t(9;11), other 11q23 translocations, abnormalities of chromosome 5/7, trisomy 8 alone, normal karyotype, single random, and multiple (defined as 2 or more) abnormalities. The DS AML samples were excluded from the subgroup analysis. Samples with chromosome 5/7 abnormalities were median 3.9-fold (P ‫؍‬ .01) more resistant to cytarabine than other AML samples. The t(9;11) samples were more sensitive to cytarabine (median 2.9-fold, P ‫؍‬ .002), etoposide (13.1-fold, P ‫؍‬ .001), the anthracyclines (2.9-to 8.0-fold, P < .01), and 2-chlorodeoxyadenosine (10.0-fold, P ‫؍‬ .002) than other AML samples. The trisomy 8 and t(15;17) groups were too small for meaningful analysis. All other genetic subgroups did not show specific resistance profiles.Overall, we found no differences in drug resistance in samples taken at diagnosis between patients remaining in continuous complete remission (CCR) versus the refractory/relapsed patients. Within several genetic subgroups, however, relapsed/refractory patients were more cytarabine resistant when compared with patients remaining in CCR, but numbers were small and the results were not significant. We conclude that some, but not all, cytogenetic subgroups in childhood AML display specific drug-resistance profiles. (Blood. 2002;100:3352-3360)

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Cellular drug resistance in acute myeloid leukemia: literature review and preliminary analysis of an ongoing collaborative study

Cited by 27 publications

References 18 publications

Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia

Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities

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