P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia

Sauerbrey, Axel; Zintl, F; Volm, M

doi:10.1038/bjc.1994.462

Cited by 63 publications

(36 citation statements)

References 36 publications

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“…Although the clinical significance of P-gp has been to necrotic death. Using the Kolmogoroff-Smirnoff test we described in some reports, 15,16 others did not 17,18 suggesting found that only unaided spontaneous apoptosis after 24 h the existence of non-P-gp-mediated mechanisms of resistance. incubation in vitro was significantly different (D = 0.7, Despite the correlation of induction of apoptosis by DNR ␣ = 0.05).…”

Section: Figurementioning

confidence: 93%

Apoptosis and resistance to daunorubicin in human leukemic cells

1997

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We compared test methods based on specific mechanisms of some interest as a novel approach for the determination of daunorubicin (DNR) resistance to more global procedures.chemosensitivity. [4][5][6] Assessment of P-glycoprotein (P-gp) expression and function Expression of P-glycoprotein (P-gp), accumulation of dau- then performed with a set of leukemic blood samples from 18Low proficiency of MNC to undergo apoptosis and low proliferative activity rather than P-gp-mediated MDR correlated with different patients. and human HL-60 promyelocytic leukemia cells were used.

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Section: Figurementioning

confidence: 93%

Apoptosis and resistance to daunorubicin in human leukemic cells

1997

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“…[9][10][11][12] Some show that its expression might be related to poor survival or risk of relapse, whereas others show no prognostic significance. [13][14][15][16][17][18][19][20] Studies using cyclosporins to modulate MDR [21][22][23][24][25] have been performed in children with AML or retinoblastoma.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

et al. 2002

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The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity. Leukemia (2002) 16, 920-927.

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“…37 Inconsistent data about the contribution of P-gp to drug resistance and treatment outcome have also been reported in childhood acute leukemia. 23,[38][39][40][41][42] We recently showed that expression of P-gp and MRP did not correlate with the intracellular DNR concentration and in vitro resistance to DNR in a large series of childhood ALL samples. 17,43 In contrast, the expression of LRP inversely correlated with the in vitro cytotoxicity and intracellular concentration of DNR.…”

Section: Discussionmentioning

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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P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia

Cited by 63 publications

References 36 publications

Apoptosis and resistance to daunorubicin in human leukemic cells

Apoptosis and resistance to daunorubicin in human leukemic cells

Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

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

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