BIOCHEMICAL MODULATION OF CLASSICAL MULTIDRUG-RESISTANCE BY BIBW22BS,A POTENT DERIVATIVE OF DIPYRIDAMOLE

Background: Modulators of the 'classical' multidrug resistance (mdr) p henotype have low efficacy in patients with solid tumors. We analyzed BIBW22BS, is(cis-2,6-dimethyl-morpholino)-6-phenylpteridine, a derivat ive of dipyridamole, for its higher potential to modulate mdr. Materia ls and methods: Four human malignant cell lines: BRO, A2780, GLC4, SW1 573, the Pgp-positive sublines: BRO/mdr1.1, 2780AD and the non-Pgp sub lines: GLC4/ADR, SW1573/2R120 were used in vitro to investigate BIBW22 BS as a modulator of the antiproliferative effects of vincristine and doxorubicin and to compare the potency of BIBW22BS with that of dipyri damole, verapamil, bepridil and flunarizine. BRO/mdr1.1 s.c. well-esta blished xenografts in nude mice were used to study the modulating prop erties 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 r esistance in the Pgp-positive sublines. Reversal of resistance was obt ained in a dose-dependent manner and was complete at concentrations of 0.5-2.5 muM. At non-toxic, equimolar concentrations of 1.0 muM BIBW22 BS showed higher modulating potency than the calcium-channel blockers. BIBW22BS did not affect resistance in the non-Pgp sublines. BRO/mdr1. 1 s.c. xenografts have stable multidrug-resistance characteristics upo n serial transplantation. BIBW22BS, vincristine, or doxorubicin as sin gle agents were not effective in vivo, while the addition of BIBW22BS could significantly reduce the tumor growth expressed as the T/C% of v incristine from 109% to 48% and that of doxorubicin from 55% to 32%. H owever, reversal of vincristine resistance in BRO/mdr1.1 xenografts wa s not complete when compared to the efficacy of vincristine in BRO xen ografts. Conclusion: The results encourage the further preclinical dev elopment of BIBW22BS as a modulator of 'classical' multidrug resistanc e in cancer patients.