Nakajima Masahide, Hayashi Kazutaka, Egi Yasuhiro, Katayama Ken-ichi, Amano Yusaku, Uehata Masayoshi, Ohtsuki Makio, Fujii Akihiro, Oshita Koh-ichi, Kataoka Hirotoshi, Chiba Kenji, Goto Nobuharu, Kondo Takao
Pharmaceuticals Research Unit, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, 227-0033 Yokohama, Japan.
Cancer Chemother Pharmacol. 2003 Oct;52(4):319-24. doi: 10.1007/s00280-003-0641-9. Epub 2003 May 29.
Rho-associated coiled-coil-forming protein kinase (ROCK) is pivotally involved in invasion by tumor cells and their evolution to metastasis. We have developed a novel inhibitor of ROCK, Wf-536 [(+)-(R)-4-(1-aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride]. In the present study, we investigated its effect on in vitro invasion and in vivo pulmonary metastasis of B16 melanoma.
The following were evaluated: the anti-invasive effect of Wf-536 against the motility of mouse B16BL6 melanoma cells through a culture insert layered with reconstituted basement membrane (Matrigel); the cytotoxic effect of Wf-536 in the same cell line; the antimetastatic effect of Wf-536, administered by osmotic pump, on spontaneous pulmonary metastasis following subcutaneous injection of B16BL6 melanoma in mice; and the inhibitory effect of orally administered Wf-536, alone or in combination with the antineoplastic drug paclitaxel, on pulmonary metastasis of intravenously injected B16F10 melanoma in mice.
Wf-536 inhibited in vitro invasion by B16BL6 cells significantly and in a concentration-dependent manner and displayed an anti-invasive effect under conditions of both chemotaxis and chemokinesis. No cytotoxic effect was observed at any of the concentrations used. In vivo, Wf-536 administration suppressed tumor colony formation on the lung surface in a dose-dependent manner (0.3-3 mg/kg per day), with a metastasis inhibition rate of 95% at 3 mg/kg per day. In experimental metastasis of B16F10 melanoma, oral administration of Wf-536 significantly decreased tumor colony formation in the lung, with an inhibition rate of 41% at 3 mg/kg per day. The inhibition rate of paclitaxel (5 mg/kg per day) was 27%. The combination of Wf-536 and paclitaxel produced a synergistic effect on B16F10 metastasis and a 68% inhibition rate. Wf-536 administration at the doses used did not alter body weight, blood pressure or the health of treated animals as compared to vehicle-treated controls.
The results suggest that Wf-536 is a potentially valuable drug for preventing tumor metastasis both in monotherapy and in combination with an antineoplastic drug.
Rho相关卷曲螺旋形成蛋白激酶（ROCK）在肿瘤细胞侵袭及其向转移的演变过程中起关键作用。我们开发了一种新型的ROCK抑制剂Wf-536 [（+）-（R）-4-（1-氨基乙基）-N-（4-吡啶基）苯甲酰胺单盐酸盐]。在本研究中，我们研究了其对B16黑色素瘤体外侵袭和体内肺转移的影响。
评估以下内容：Wf-536通过铺有重组基底膜（基质胶）的培养插入物对小鼠B16BL6黑色素瘤细胞运动性的抗侵袭作用；Wf-536在同一细胞系中的细胞毒性作用；通过渗透泵给药的Wf-536对小鼠皮下注射B16BL6黑色素瘤后自发肺转移的抗转移作用；以及单独或与抗肿瘤药物紫杉醇联合口服Wf-536对小鼠静脉注射B16F10黑色素瘤肺转移的抑制作用。
Wf-536显著且呈浓度依赖性地抑制B16BL6细胞的体外侵袭，并在趋化性和趋动性条件下均显示出抗侵袭作用。在所使用的任何浓度下均未观察到细胞毒性作用。在体内，给予Wf-536以剂量依赖性方式（每天0.3 - 3 mg/kg）抑制肺表面的肿瘤集落形成，每天3 mg/kg时转移抑制率为95%。在B16F10黑色素瘤的实验性转移中，口服Wf-536显著减少肺中的肿瘤集落形成，每天3 mg/kg时抑制率为41%。紫杉醇（每天5 mg/kg）的抑制率为27%。Wf-536与紫杉醇联合对B16F10转移产生协同作用，抑制率为68%。与载体处理的对照组相比，以所使用的剂量给予Wf-536不会改变治疗动物的体重、血压或健康状况。
结果表明，Wf-536无论是单药治疗还是与抗肿瘤药物联合使用，都是一种预防肿瘤转移的潜在有价值的药物。
