Effect of daunorubicin, carminomycin, idarubicin and 4-demethoxydaunorubicinol against human normal myeloid stem cells and human malignant cells In vitro

Dodion, Pierre; Sanders, Charlotte; Rombaut, W.; Mattelaer, Marie Anne; Rozencweig, Marcel; Stryckmans, Pierre; Kenis, Yvon

doi:10.1016/0277-5379(87)90058-7

Cited by 18 publications

(9 citation statements)

References 16 publications

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“…Besides the well-characterized anthracycline resistance mediated by the expression of the MDR-1 gene product, other mechanisms can be important in resistance to anthracyclines, including topoisomerase II alterations and increased concentrations of reduced glutathione (Pommier 1993;Schneider et al 1990;Gessner et al 1990;Nair et al 1990). IDA is an anthracycline that has shown better in vitro cytotoxicity than DNR against tumor cell lines (Dodion et al 1987), and some clinical studies have shown a signi®cant increase in the response rate after induction chemotherapy with AraC and IDA instead of DNR of patients with AML (Berman et al 1991;Vogler et al 1992;Wiernik et al 1992). However, in these studies suboptimal doses of daunorubicin were used.…”

Section: Discussionmentioning

confidence: 98%

In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia

Schröder

Kasimir‐Bauer

Seeber

et al. 2000

Journal of Cancer Research and Clinical Oncology

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Recent results show that the intracellular uptake pattern of idarubicin (IDA) in multidrug-resistant (MDR) cells is nearly identical to that seen in the drug-sensitive parent cell line, whereas the MDR cells have minimal daunorubicin (DNR) uptake compared with the drug-sensitive parent cells. It is known that the major metabolite of IDA, idarubicinol (IDA-OL), has nearly the same cytotoxicity as IDA, while the cytotoxicity of daunorubicinol (DNR-OL) is about 1/30th of that of DNR. We examined the effect of the MDR modifiers verapamil and dexniguldipine on the efflux of IDA, DNR and their hydroxylated metabolites IDA-OL and DNR-OL in blast populations of acute myeloid leukemia (AML), in the MDR-negative cell line CEM-CCRF and in their MDR-positive counterpart (CEM-VBL). All patients with relapsed or persistent AML had been pretreated with IDA and cytosine arabinoside. The efflux of the anthracyclines was estimated by flow cytometry. A total of 36 patients with AML were investigated; 18 out of 36 AML blast populations showed an efflux of DNR, DNR-OL and IDA-OL. The efflux of DNR, DNR-OL and particularly IDA-OL could be reversed by 10 microM verapamil or 1 microM dexniguldipine. For IDA we found an effusion of 40 +/- 11% in all blast populations which could not be significantly inhibited by the modulators. Similar results for IDA were found in the MDR-positive cell line (CEM-VBL 100) and in their MDR-negative counterpart (CEM-CCRF). The incubation of CEM-CCRF cells with DNR, DNR-OL, IDA-OL and especially IDA led to MDR induction as determined by reverse transcription/polymerase chain reaction analysis with MDR-specific primer and by cellular efflux studies. We conclude that the outcome of chemotherapy with idarubicin is influenced by MDR, although IDA is not essentially MDR-dependent itself, but because IDA-OL is actively involved in multidrug resistance. Further investigations should consider the question of whether the combination of IDA and MDR modifiers can enhance the serum level of the active metabolite IDA-OL and can reverse the MDR pattern in cells treated with IDA.

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Section: Discussionmentioning

confidence: 98%

In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia

Schröder

Kasimir‐Bauer

Seeber

et al. 2000

Journal of Cancer Research and Clinical Oncology

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“…On an equimolar basis, in vitro data indicate that IDA is more cytotoxic than DNR to leukemic blasts and normal hematopoietic stem cells [9][10][11][12]. While some investigators [9,10] have found that normal marrow precursors were more sensitive to IDA than AML blasts, two other in vitro studies revealed no difference in the sensitivity of normal and leukemic precursors to IDA [11,12].…”

Section: Introductionmentioning

confidence: 98%

“…While some investigators [9,10] have found that normal marrow precursors were more sensitive to IDA than AML blasts, two other in vitro studies revealed no difference in the sensitivity of normal and leukemic precursors to IDA [11,12].…”

Section: Introductionmentioning

confidence: 99%

Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin

Seipelt¹,

Hofmann²,

Martin³

et al. 1998

Annals of Hematology

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The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n = 6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n = 10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (< 500 neutrophils/microl) following HDara-C/DNR was 31.2 +/- 16 days (mean +/- SEM) in the IDA group compared with 18.7 +/- 5 days in the DNR group (p < .001 Mann-Whitney U-test). The duration 'of thrombocytopenia (platelets < 25000/microl) was 34.8 +/- 20 days in the IDA group vs. 18.5 +/- 6 days in the DNR group (p < .005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 +/- 24 vs. 6.9 +/- 5.2 days). A greater incidence, length (11 +/- 8 vs. 1.2 +/- 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials.

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“…IDA doses that were equiactive in terms of systemic exposure to the parent drug and metabolite concurrently. Previous studies indicate that the metabolite has 50% of the cytotoxic activity of the parental compound in normal human bone marrow progenitors 15 and in some cancer cell lines 9,11 . Therefore, it turned out that approximately the same total AUC 24h (IDA AUC 24h + 1 ⁄ 2 IDOL AUC 24h ) was reached with an oral dose/m 2 of IDA about 2.5-fold greater than the corresponding i.v.…”

Section: Discussionmentioning

confidence: 99%

“…This probably has some clinical effects. In fact, even if IDOL has not been tested in the clinical setting yet, its activity against tumor cells in vitro has been recognized 9,11 and it has been reported that its cytotoxic activity is about half that of the parent compound 9,11,15 . Finally, another aspect to be considered is the fluctuation of drug plasmatic concentration after oral administration.…”

Section: Pharmacokinetic Comparison Of 120-hour Infusionmentioning

confidence: 97%

Pharmacokinetic Comparison of 120-Hour InfusionVersusHyperfractionated Oral Administration of Idarubicin

Toffoli

Sorio

Basso

et al. 2004

Journal of Chemotherapy

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The aim of this study was to compare the pharmacokinetics of idarubicin (IDA) and its active metabolite idarubicinol (IDOL) after chronic oral and continuous intravenous (i.v.) IDA administration in order to establish the oral doses needed to reach the i.v. equiactive plasma drug exposure. The pharmacokinetic profile of IDA and IDOL was investigated in 23 patients receiving 12 mg/m2 IDA by 120-h i.v. infusion (2.4 mg/m2/day) combined with cyclophosphamide, etoposide and prednisone in comparison to 28 patients receiving oral IDA doses ranging from 2 to 10 mg/day for 21 days in a phase I study. We found that IDA AUC24h/dose/m2 was 4.7-fold greater during i.v. than oral administration, whereas IDOL AUC24h/dose/m2 was only about 2-fold higher after i.v. administration. The metabolic ratio between IDOL AUC24h and IDA AUC24h in plasma was about 3-fold higher after oral administration. Based on these results we were able to estimate that equiactive plasma drug exposure was reached with an approximately 2.5-fold greater oral dose/m2 of IDA than the corresponding i.v. dose.

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Effect of daunorubicin, carminomycin, idarubicin and 4-demethoxydaunorubicinol against human normal myeloid stem cells and human malignant cells In vitro

Cited by 18 publications

References 16 publications

In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia

In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia

Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin

Pharmacokinetic Comparison of 120-Hour InfusionVersusHyperfractionated Oral Administration of Idarubicin

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