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

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Abstract
Modulators of the ‘classical’ multidrug resistance (mdr) phenotype have low efficacy in patients with solid tumors. We analyzed BIBW22BS, 4-[N-(2-hydroxy-2-met-hyl-propyl)-ethanolamino]-2,7-bis(cis-2,6-dimethyl-morpho-lino)- 6-phenylpteridine, a derivative of dipyridamole, for its higher potential to modulate mdr. Four human malignant cell lines: BRO, A2780, GLC4, SW1573, the Pgp-positive sublines: BRO/mdrl.l, 2780AD and the non-Pgp sublines: GLC4/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.l s.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 × 2. 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.l s.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.l xenografts was not complete when compared to the efficacy of vincristine in BRO xenografts. The results encourage the further preclinical development of BIBW22BS as a modulator of ‘classical’ multidrug resistance in cancer patients.