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.

译文

吗啉代-二硅氧烷 (ALIS-409) 和哌嗪代-二硅氧烷 (ALIS-421) 化合物被开发为各种类型癌细胞的多药耐药性抑制剂。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和正常细胞共存的影响。评估了这两种化合物对Raji细胞培养物中十四烷酰-佛波醇-乙酸酯 (TPA) 诱导的爱泼斯坦-巴尔病毒即刻早期抗原 (ebv-ea) 表达的抑制作用。该方法被称为抗肿瘤作用的初步筛选测试,低于 (IC50) 浓度。在高达1000 μ g/ml的浓度范围内,ALIS-409比ALIS-421更有效地抑制ebv-ea (100 μ g/ml) 和促进肿瘤。然而,这两种化合物都不能显着降低肿瘤的促进,表现为抑制TPA诱导的肿瘤抗原激活。根据体外结果,在两阶段小鼠皮肤癌发生研究中,在体内研究了两种二硅氧烷对小鼠皮肤肿瘤的影响。施用二甲基苯并蒽 (DMBA; 390 nmol) 作为肿瘤引发剂,然后暴露于作为肿瘤促进剂的TPA (1.7 nmol/l)。实验表明,与DMBA加TPA处理的小鼠的阳性对照相比,浓度为85 nmol/l的ALIS-409在体外具有弱的ebv-ea抑制作用和中等的抗肿瘤活性。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。与对照未处理的细胞群体相比,在存在ALIS-409的情况下,MCF7乳腺癌和MRC5正常成纤维细胞的混合群体中肿瘤细胞的生长速率降低。在DMBA诱导和TPA促进的体内肿瘤形成中,两种二硅氧烷在化学预防方面均有效。作者认为,ALIS409抑制肿瘤细胞和成纤维细胞相互作用可能对抗基质治疗的发展具有一定的意义。

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