Stearns M E, Wang M, Fudge K
Department of Pathology, Medical College of Pennsylvania, Philadelphia 19129.
Cancer Res. 1993 Jul 1;53(13):3073-7.
Liarozole fumarate (R85,246), a novel benzimidazole derivative, reduced s.c. and bone metastasis tumor growth by the androgen-independent PC-3ML-B2 human prostatic carcinoma clone in SCID mice. The drug inhibited cell invasion of Matrigel in Boyden chamber chemotactic assays and the secretion of type IV collagenase. In vitro, liarozole failed to inhibit cell proliferation and cell attachment to various substrates (Matrigel, laminin, type IV collagen, and fibronectin). In vivo, the drug also blocked type IV collagenase production in established s.c. tumors. Liarozole has been postulated by others (R. De Coster, W. Wouters, R. Van Ginckel, D. End, et al. J. Steroid Biochem. Mol. Biol., 43: 197-201, 1992) to inhibit retinoic acid catabolism. Our data indicate that liarozole treatment can increase the tumor retinoic acid levels in vivo. Studies of retinoic acid revealed that the drug independently reduced tumor growth in vivo and inhibited cell invasion of Matrigel and the secretion of collagenase IV. Surprisingly, liarozole and retinoic acid failed to exhibit measurable synergistic activity both in vitro and in vivo. Taken together these data suggest that liarozole might inhibit retinoic acid catabolism in vivo and consequently have significant therapeutic value as an anti-prostatic tumor agent.
富马酸来罗唑（R85,246），一种新型苯并咪唑衍生物，可减少雄激素非依赖性PC-3ML-B2人前列腺癌克隆在SCID小鼠中的皮下和骨转移肿瘤生长。该药物在Boyden室趋化分析中抑制基质胶的细胞侵袭以及IV型胶原酶的分泌。在体外，来罗唑未能抑制细胞增殖以及细胞与各种底物（基质胶、层粘连蛋白、IV型胶原和纤连蛋白）的附着。在体内，该药物还可阻断已形成的皮下肿瘤中IV型胶原酶的产生。其他人（R. De Coster、W. Wouters、R. Van Ginckel、D. End等人，《类固醇生物化学与分子生物学杂志》，43: 197 - 201, 1992）推测来罗唑可抑制视黄酸分解代谢。我们的数据表明，来罗唑治疗可在体内提高肿瘤视黄酸水平。对视黄酸的研究显示，该药物可独立减少体内肿瘤生长，并抑制基质胶的细胞侵袭以及IV型胶原酶的分泌。令人惊讶的是，来罗唑和视黄酸在体外和体内均未表现出可测量的协同活性。综合这些数据表明，来罗唑可能在体内抑制视黄酸分解代谢，因此作为一种抗前列腺肿瘤药物具有显著的治疗价值。
