Biochemical modulation of ‘classical’ multidrug resistance by BIBW22BS, a potent derivative of dipyridamole

Jansen, W. J. M.; Pinedo, H.M.; Kuiper, C. M.; Lincke, Carsten R.; Bamberger, Uwe; Heckel, Armin; Boven, E.

doi:10.1093/oxfordjournals.annonc.a058978

Cited by 11 publications

(9 citation statements)

References 21 publications

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“…1.1 and 2780k" at concentrations that were not toxic, as established earlier (Jansen et al, 1994). The dipyridamole derivative BIBW22BS (1 gM) and the calcium-channel blockers verapamil (10 gM) and dexniguldipine (1 gM) did not increase the antiproliferative effects of carboxylesterase-activated CPT-l1 and SN-38 in the parent cell lines BRO and A2780 (Table 3).…”

Section: P-gp Modulatorssupporting

confidence: 68%

“…Solid tumours arising at the inoculation site were transferred as tissue fragments of 2-to 3-mm diameter through a small incision into both flanks of 8-to 10-week-old mice. A previous study demonstrated the retention of the multidrug-resistant phenotype in s.c. BRO/mdrl.1 xenografts > 15 serial passages (Jansen et al, 1994). For the 2780-cells, a CPT-11 sensitivity in relation to P-gp and MRP expression 361 For in vivo use, CPT-l 1 was further diluted in 0.9% sodium chloride to 2 mg ml.…”

Section: In Vivo Sensitivitymentioning

confidence: 99%

“…The 20 mg kg-' dose was the maximum-tolerated dose of CPT-1 1 given daily x 5, as based on the occurrence of a reversible weight loss of approximately 10% of the initial weight within the first 2 weeks after day 0. Vincristine 1 mg kg-' and doxorubicin 8 mg kg-' given intravenously weekly x 2 were the maximum-tolerated doses as described earlier (Jansen et al, 1994).…”

Section: In Vivo Sensitivitymentioning

confidence: 99%

“…Most malignant cell lines and drug-resistant sublines described in Table 1 have been characterized earlier for their sensitivity to vincristine and doxorubicin (Jansen et al, 1994). Except for vincristine in GLC4/ADR and SW1573/Sl (MRP), all sublines were resistant against vincristine and doxorubicin.…”

Section: Antiproliferative Effects Of Cpt-1 1 In Vitromentioning

confidence: 99%

“…Previously, the activity of vincristine and doxorubicin has been determined in the P-gp-positive xenografts and the corresponding parent xenografts (Jansen et al, 1994). A summary of these data is given in Table 4, showing the retention of the resistance against vincristine and doxorubicin in the P-gp-positive tumours.…”

Section: In Vivo Sensitivitymentioning

confidence: 99%

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CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Jansen

Hulscher²,

Ark-Otte³

et al. 1998

Br J Cancer

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Summary The relevance of P170-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) for the sensitivity to CPT-11 was investigated in human malignant cell lines as well as in human tumour xenografts. In vitro, the P-gp-positive sublines BRO/mdrl.1 (transfected with MDR1) and 2780AD were slightly cross-resistant against carboxylesterase-activated CPT-11. Cross-resistance against SN-38 was present in 2780AD cells, but not in BRO/mdrl.1 cells. The P-gp modulators BIBW22BS, verapamil and dexniguldipine partly reversed the resistance against CPT-11 in the P-gp-positive sublines. BIBW22BS was the most effective modulator in the reversal of the resistance against carboxylesterase-activated CPT-11 as well as against in the 2780AD subline. In contrast to doxorubicin and vincristine, the BRO/mdrl.1 xenografts were at least as sensitive to CPT-11 as the BRO xenografts. The 2780AD xenografts were slightly less sensitive than the parent tumours, but there was no difference in topoisomerase I DNA unwinding activity. Therefore, the high retention of the multidrugresistant phenotype of 2780AD cells in vivo may be the cause of the low cross-resistance against CPT-11. The MRP-positive subline GLC4/ADR was cross-resistant against carboxylesterase-activated CPT-11 and SN-38. GLC4/ADR cells, however, demonstrated a twofold lower topoisomerase I activity than GLC4 cells. Cross-resistance against the camptothecin derivatives was not apparent in the MRPtransfected subline of SW1573/Si. In conclusion, P-gp-positive cells show a low cross-resistance against CPT-11/SN38, which is only apparent with high P-gp expression in vivo. MRP does not seem to play a role in the sensitivity to

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Section: P-gp Modulatorssupporting

confidence: 68%

Section: In Vivo Sensitivitymentioning

confidence: 99%

Section: In Vivo Sensitivitymentioning

confidence: 99%

Section: Antiproliferative Effects Of Cpt-1 1 In Vitromentioning

confidence: 99%

Section: In Vivo Sensitivitymentioning

confidence: 99%

See 3 more Smart Citations

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Jansen

Hulscher²,

Ark-Otte³

et al. 1998

Br J Cancer

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Multifunctional Modulators of Drug Resistance

Murren¹,

Rappa²,

Cheng³

1996

Drug Resistance

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Modulation of multidrug resistance by BIBW22BS in blasts of de novo or relapsed or persistent acute myeloid leukemia ex vivo

Schröder

Esteban

Müller

et al. 1996

J Cancer Res Clin Oncol

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The phenylpteridine derivative BIBW22BS (BIBW22) is a potent modulator of multidrug resistance (MDR). We investigated BIBW22 in comparison to dexniguldipine and verapamil as modifier of MDR in blasts of de novo, relapsed or persistent acute myeloid leukemia (AML) in vitro. All patients with relapsed or persistent AML had been pretreated with idarubicin and cytosine arabinoside. The degree of MDR was determined by efflux kinetics of rhodamine 123 (R123), daunorubicin, and idarubicin measured by flow cytometry (FACS). A total of 51 patients with AML, 25 de novo and 26 relapsed or persistent, were investigated. While only 6 out of 25 de novo AML blast populations showed moderate efflux of R123 and daunorubicin, 17 out of 26 blast populations of relapsed or persistent AML had an efflux between 20% and 44% within 15 min ex vivo. This efflux could be significantly inhibited by 1 microM BIBW22, 1 microM dexniguldipine, or 10 microM verapamil. For idarubicin we found an effusion of 40+/-9% within 15 min in all blast populations that could not be inhibited by the modulators. Clinically achievable drug concentrations causing only moderate side-effects are in the range of 0.5 microM dexniguldipine and 3 microM verapamil. Up to now, BIBW22 has not been investigated clinically. Thus the potential toxicity of concentrations of 0.5-1 microM BIBW22, sufficient for an optimal efflux inhibition ex vivo, is not known yet. We conclude from our ex vivo investigations in blast populations of de novo, relapsed or persistent AML that BIBW22 is a potent modulator of MDR.

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Biochemical modulation of ‘classical’ multidrug resistance by BIBW22BS, a potent derivative of dipyridamole

Abstract: The results encourage the further preclinical development of BIBW22BS as a modulator of 'classical' multidrug resistance in cancer patients.

Cited by 11 publications

References 21 publications

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Multifunctional Modulators of Drug Resistance

Modulation of multidrug resistance by BIBW22BS in blasts of de novo or relapsed or persistent acute myeloid leukemia ex vivo

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