Borgström P, Torres Filho I P, Hartley-Asp B
La Jolla Institute for Experimental Medicine, CA 92037, USA.
Anticancer Res. 1995 May-Jun;15(3):719-28.
Linomide has antitumor effects when administered in vivo but not in vitro. Recent data indicate that at least part of this effect can be attributed to anti-angiogenic properties. The aim of the present investigation was to study the anti-angiogenic effects of Linomide on early tumor-induced angiogenesis in vivo, using a newly developed skinfold chamber technique in the mouse, and to relate this to the effect of Linomide on the number of metastases that develop from a s.c. implanted tumor. Tumor spheroids of Lewis lung cell carcinoma (LLC) with a diameter of about 800 microns were implanted in dorsal skinfold chambers inserted on CB6/Fl mice. Tumor cells were pre-labelled with a fluorescent vital dye (CMTMR), which allowed the estimation of the growth of the implanted tumor spheroids. Linomide, given orally from day 7 to day 11, reduced the incidence of lung metastasis arising from LLC tumors at day 21 in a dose-dependent manner, a 55% reduction being found at a dose of 50 mg/kg/day (N = l9 for the controls and N = 10 for treatment groups). In the dorsal skinfold chamber, the vascular network in Linomide treated animals (100 mg/kg/day, N = 22) was more heterogenous, large areas within the tumor being completely avascular; in addition, capillary density at the tumor site was reduced by 34% 6 days after implantation and by 39% after 14 days. In the control group (N = 16), tumor volume doubling time was not significantly different in the early avascular part of the observation period as compared to the later vascular phase; this indicates that the growth of these micro-tumors in the early avascular phase is not angiogenesis dependent. However, in the Linomide treated animals, tumor volume doubling time was significantly prolonged by 42% during the later part of the observation period. Taken together, the data indicate that the prolongation of the tumor doubling time is due to the anti-angiogenic activity of Linomide.
利索胺在体内给药时有抗肿瘤作用，但在体外则无此作用。最近的数据表明，这种作用至少部分可归因于其抗血管生成特性。本研究的目的是利用一种新开发的小鼠皮褶箱技术，研究利索胺对体内早期肿瘤诱导的血管生成的抗血管生成作用，并将其与利索胺对皮下植入肿瘤发生转移的数量的影响联系起来。将直径约800微米的Lewis肺癌（LLC）肿瘤球体植入CB6/Fl小鼠背部的皮褶箱中。肿瘤细胞预先用荧光活性染料（CMTMR）标记，这使得能够估计植入的肿瘤球体的生长情况。从第7天至第11天口服利索胺，以剂量依赖的方式降低了LLC肿瘤在第21天发生肺转移的发生率，在剂量为50毫克/千克/天时发现降低了55%（对照组N = 19，治疗组N = 10）。在背部皮褶箱中，接受利索胺治疗的动物（100毫克/千克/天，N = 22）的血管网络更加不均匀，肿瘤内的大片区域完全无血管；此外，植入后6天肿瘤部位的毛细血管密度降低了34%，14天后降低了39%。在对照组（N = 16）中，在观察期的早期无血管部分与后期血管期相比，肿瘤体积倍增时间无显著差异；这表明这些微肿瘤在早期无血管期的生长不依赖于血管生成。然而，在接受利索胺治疗的动物中，在观察期的后期肿瘤体积倍增时间显著延长了42%。综上所述，数据表明肿瘤倍增时间的延长是由于利索胺的抗血管生成活性。
