Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia

Pieters, Rob; Huismans, D. R.; Loonen, A. H.; Hählen, K.; Berg, Anna; Wering, E. R. Van

doi:10.1016/0140-6736(91)91029-t

Cited by 208 publications

(117 citation statements)

References 22 publications

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“…This assay has been successfully used to predict clinical outcome in childhood leukemias. 6,7 As far as its use in adult AML, two pilot studies have shown that in vitro resistance to DNR was significantly related to non-response, 28,29 whereas in vitro resistance to cytarabine was associated with short and longterm outcome. 28,29 Prospective studies addressing the clinical relevance of this assay are clearly needed.…”

Section: Rationale For the Methodologymentioning

confidence: 99%

“…6,7,19 Briefly, cells were incubated in microtiter plates for 4 days with six DNR concentrations (0.002-2 g/ml) in duplicate wells. Results are expressed as DNR LC 50 values: the DNR concentration lethal to 50% of the cells as compared to cells from the same sample cultured in the same plate without DNR.…”

Section: Mtt Cytotoxicity Testmentioning

confidence: 99%

“…Among these are the differential staining cytoxicity test, 2,3 in vitro autonomous proliferation 4 and the 'MTT' chemosensitivity test. 5,6 The latter test has been applied to predict the clinical response to combination therapy in childhood lymphoblastic leukemia. 6,7 In adult leukemias, including AML, more effort has been put into the application of mechanism-based drug resistance tests.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 The latter test has been applied to predict the clinical response to combination therapy in childhood lymphoblastic leukemia. 6,7 In adult leukemias, including AML, more effort has been put into the application of mechanism-based drug resistance tests. As far as the anthracyclines are concerned, tests which measure the intracellular accumulation of the anthracycline in patients' myeloblasts have been initially explored.…”

Section: Introductionmentioning

confidence: 99%

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1999

Leukemia

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Section: Rationale For the Methodologymentioning

confidence: 99%

Section: Mtt Cytotoxicity Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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1999

Leukemia

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“…The risk of treatment failure is related to cellular resistance to different classes of drugs such as anthracyclines, glucocorticoids, L-asparaginase and vinca alkaloids. [1][2][3] Strategies to circumvent drug resistance include the development of new drugs and modulators of resistance. In childhood ALL, cross-resistance to anthracyclines is often Correspondence observed, including new drugs such as idarubicin and aclarubicin.…”

Section: Introductionmentioning

confidence: 99%

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

et al. 1998

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Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 M PSC 833 (P = 0.025), 1.5-fold using 4 M CsA (P = 0.003) and 1.6-fold using 6 M Vp (P = 0.012) whereas the adverse effect of 25 M genistein was median 1.8-fold (P Ͻ 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of Pgp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.

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In vitro culture with prednisolone increases BCL-2 protein expression in adult acute lymphoblastic leukemia cells

et al. 1996

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The presence of BCL-2 gene rearrangement has been detected also in cellular populations lacking the t(14;18) chromosomal translocation, such as B-lineage acute lymphoblastic leukemia (ALL) cells. It has been reported that overexpression of BCL-2 is related to resistance to glucocorticoid-induced apoptosis. In this study, we aimed to evaluate whether in vitro culture with prednisolone (PDN) could modify the expression of BCL-2 protein. ALL cells from 21 patients were incubated for 72 hr with or without a minimally lethal (IC12) dose of PDN. In vitro culture with PDN did not affect the percentage of positive cells, even though the mean fluorescence index was significantly increased (P = 0.0001), thus indicating a higher level of protein production. These data could suggest a possible mechanism of drug resistance after treatment with PDN.

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Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia

Cited by 208 publications

References 22 publications

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The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

In vitro culture with prednisolone increases BCL-2 protein expression in adult acute lymphoblastic leukemia cells

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