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

1994; Elsevier BV; Volume: 5; Issue: 8 Linguagem: Inglês

10.1093/oxfordjournals.annonc.a058978

1569-8041

W.J.M. Jansen, Herbert M. Pinedo, C.M. Kuiper, Carsten R. Lincke, U. Bamberger, Armin Heckel, E. Boven,

Pharmacological Effects and Toxicity Studies

Background: Modulators of the 'classical' multidrug resistance (mdr) phenotype have low efficacy in patients with solid tumors.We analyzed BIBW22BS, 4-[N-(2-hydroxy-2-methyl-propyl)-ethanolamino]-2,7-bis(cis-2,6-dimethyl-morpholino)-6-phenylpteridine, a derivative of dipyridamole, for its higher potential to modulate mdr.Materials and methods: Four human malignant cell lines: BRO, A2780, GLC 4 , SW1573, the Pgp-positive sublines: BRO/mdrl.l,2780*° and the non-Pgp sublines: GLC 4 / ADR, SW1573/2R120 were used in vitro to investigate BIBW22BS as a modulator of the antiproliferative effects of vincristine and doxorabicin and to compare the potency of BIBW22BS with that of dipyridamole, verapamil, bepridil and flunarizine.BRO/mdrl.ls.c.well-established xenografts in nude mice were used to study the modulating properties of BIBW22BS 50 mg/kg i.v.followed after one h by vincristine 1 mg/kg i.p. or doxorubicin 8 mg/kg i.p. weekly x 2.Results: BIBW22BS was 20-to 100-fold more potent than dipyridamole in the reversal of resistance in the Pgp-positive sublines.Reversal of resistance was obtained in a dose-dependent manner and was complete at concentrations of 0.5-2.5 (iM.At non-toxic, equimolar concentrations of 1.0 piM BIBW22BS showed higher modulating potency than the calcium-channel blockers.BIBW22BS did not affect resistance in the non-Pgp sublines.BRO/mdrl.ls.c.xenografts have stable multidrug-resistance characteristics upon serial transplantation.BIBW22BS, vincristine, or doxorubicin as single agents were not effective in vivo, while the addition of BIBW22BS could significantly reduce the tumor growth expressed as the T/C% of vincristine from 109% to 48% and that of doxorabicin from 55% to 32%.However, reversal of vincristine resistance in BRO/mdrl.lxenografts was not complete when compared to the efficacy of vincristine in BRO xenografts. Conclusion:The results encourage the further preclinical development of BIBW22BS as a modulator of 'classical' multidrug resistance in cancer patients.