Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Anticancer Res. 2013 May;33(5):2021-7.
Morpholino-disiloxane (ALIS-409) and piperazino-disiloxane (ALIS-421) compounds were developed as inhibitors of multidrug resistance of various types of cancer cells. In the present study, the effects of ALIS-409 and ALIS-421 compounds were investigated on cancer promotion and on co-existence of tumor and normal cells. The two compounds were evaluated for their inhibitory effects on Epstein-Barr virus immediate-early antigen (EBV-EA) expression induced by tetradecanoyl-phorbol-acetate (TPA) in Raji cell cultures. The method is known as a primary screening test for antitumor effect, below the (IC50) concentration. ALIS-409 was more effective in inhibiting EBV-EA (100 μg/ml) and tumor promotion, than ALIS-421, in the concentration range up to 1000 μg/ml. However, neither of the compounds were able to reduce tumor promotion significantly, expressed as inhibition of TPA-induced tumor antigen activation. Based on the in vitro results, the two disiloxanes were investigated in vivo for their effects on mouse skin tumors in a two-stage mouse skin carcinogenesis study. The application of dimethyl-benzanthracene (DMBA; 390 nmol) as a tumor initiator was followed by exposure to TPA (1.7 nmol/l) as a tumor promoter. The experiments showed that ALIS-409 at a concentration of 85 nmol/l had a weak EBV-EA inhibitory effect in vitro and a moderate antitumor activity, compared to the positive control of DMBA plus TPA-treated mice. Flow cytometry by differential staining demonstrated interactions in co-cultures of MCF7 breast cancer and MRC5 human lung fibroblasts. The growth rate of tumor cells in mixed populations of MCF7 breast cancer and MRC5 normal fibroblast cells was reduced in the presence of ALIS-409, as compared to the control non-treated cell populations. The two disiloxanes were moderately-effective in chemoprevention in DMBA-induced and TPA-promoted in vivo tumor formation. Authors suggest that the inhibition of tumor cell and fibroblast interaction by ALIS409 might have some perspective in the development of anti-stromal therapy.
吗啉代-二硅氧烷 (ALIS-409) 和哌嗪基-二硅氧烷 (ALIS-421) 化合物被开发为各种类型癌细胞多药耐药的抑制剂。在本研究中，研究了 ALIS-409 和 ALIS-421 化合物对癌症促进以及肿瘤细胞和正常细胞共存的影响。评估了这两种化合物对十四烷酰佛波醇-13-乙酸酯 (TPA) 在 Raji 细胞培养物中诱导的 Epstein-Barr 病毒早期抗原 (EBV-EA) 表达的抑制作用。该方法是一种抗肿瘤作用的初步筛选试验，低于 (IC50) 浓度。在高达 1000μg/ml 的浓度范围内，ALIS-409 比 ALIS-421 更有效地抑制 EBV-EA(100μg/ml)和肿瘤促进。然而，这两种化合物都不能显著降低肿瘤促进作用，表现为抑制 TPA 诱导的肿瘤抗原激活。基于体外结果，在二阶段小鼠皮肤致癌性研究中，在体内研究了两种二硅氧烷对小鼠皮肤肿瘤的作用。二甲基苯并蒽 (DMBA；390nmol) 作为肿瘤启动子的应用后，用 TPA(1.7nmol/l)作为肿瘤促进剂。实验表明，ALIS-409 在浓度为 85nmol/l 时，在体外具有较弱的 EBV-EA 抑制作用和中等的抗肿瘤活性，与 DMBA 加 TPA 处理小鼠的阳性对照相比。通过差异染色的流式细胞术证明了 MCF7 乳腺癌和 MRC5 人肺成纤维细胞共培养物中的相互作用。与对照未经处理的细胞群相比，在存在 ALIS-409 的情况下，混合培养物中 MCF7 乳腺癌肿瘤细胞的生长速度降低。两种二硅氧烷在 DMBA 诱导和 TPA 促进的体内肿瘤形成中具有中等的化学预防作用。作者认为，ALIS409 抑制肿瘤细胞和成纤维细胞相互作用可能在抗基质治疗的发展中有一定的前景。
