双嘧达莫的强效衍生物BIBW22BS对“经典”多药耐药性的生化调节作用

Biochemical modulation of 'classical' multidrug resistance by BIBW22BS, a potent derivative of dipyridamole.

作者信息

Jansen W J, Pinedo H M, Kuiper C M, Lincke C, Bamberger U, Heckel A, Boven E

机构信息

Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.

出版信息

Ann Oncol. 1994 Oct;5(8):733-9. doi: 10.1093/oxfordjournals.annonc.a058978.

DOI:10.1093/oxfordjournals.annonc.a058978

PMID:7826906

Abstract

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-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.

MATERIALS AND METHODS

Four human malignant cell lines: BRO, A2780, GLC4, SW1573, the Pgp-positive sublines: BRO/mdr1.1, 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 doxorubicin and to compare the potency of BIBW22BS with that of dipyridamole, verapamil, bepridil and flunarizine. BRO/mdr1.1 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 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 microM. At non-toxic, equimolar concentrations of 1.0 microM BIBW22BS 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 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 doxorubicin from 55% to 32%. However, reversal of vincristine resistance in BRO/mdr1.1 xenografts 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.

摘要

背景

“经典”多药耐药（mdr）表型调节剂对实体瘤患者疗效欠佳。我们分析了双嘧达莫衍生物BIBW22BS（4-[N-(2-羟基-2-甲基丙基)-乙醇胺]-2,7-双(顺式-2,6-二甲基吗啉)-6-苯基蝶啶）调节mdr的潜力。

材料与方法

体外实验采用4种人类恶性细胞系：BRO、A2780、GLC4、SW1573，Pgp阳性亚系：BRO/mdr1.1、2780AD，以及非Pgp亚系：GLC4/ADR、SW1573/2R120，研究BIBW22BS对长春新碱和阿霉素抗增殖作用的调节，并将BIBW22BS与双嘧达莫、维拉帕米、苄普地尔和氟桂利嗪的效力进行比较。采用在裸鼠中皮下接种建立良好的BRO/mdr1.1异种移植瘤，研究静脉注射50mg/kg BIBW22BS的调节特性，1小时后腹腔注射1mg/kg长春新碱或8mg/kg阿霉素，每周2次。

结果

在Pgp阳性亚系中，BIBW22BS逆转耐药的效力比双嘧达莫高20至100倍。耐药逆转呈剂量依赖性，在0.5至2.5μM浓度时完全逆转。在1.0μM无毒等摩尔浓度下，BIBW22BS的调节效力高于钙通道阻滞剂。BIBW22BS对非Pgp亚系的耐药性无影响。BRO/mdr1.1皮下异种移植瘤经连续传代后具有稳定的多药耐药特性。BIBW22BS、长春新碱或阿霉素单药在体内无效，而添加BIBW22BS可显著降低肿瘤生长，长春新碱的T/C%从109%降至48%，阿霉素的T/C%从55%降至32%。然而，与长春新碱对BRO异种移植瘤的疗效相比，BRO/mdr1.1异种移植瘤中长春新碱耐药的逆转并不完全。