Zarkovic N, Vukovic T, Loncaric I, Miletic M, Zarkovic K, Borovic S, Cipak A, Sabolovic S, Konitzer M, Mang S
Rudjer Boskovic Institute, Division of Molecular Medicine, HR-1000 Zagreb, Croatia.
Cancer Biother Radiopharm. 2001 Feb;16(1):55-62. doi: 10.1089/108497801750096041.
The activity principle of the mistletoe (Viscum album L.) phytotherapeutics could be considered as combined cytotoxic and "biological response modifying" activities (increasing host defense against cancer) that result from the activities of the plant lectins and the other biologically relevant substances. We found before that the aqueous extract Isorel, produced by Novipharm GmbH (Pörtschach, Austria) from the entire plant (planta tota) of fresh mistletoe under standardized conditions with bioassay validated batch consistency, can be valuable in experimental adjuvant cancer therapy increasing efficiency of cyclophosphamide chemotherapy. In current study we found that Isorel increases the reactivity of the tumor-bearing mice lymphocytes to the mitogens (ConA and LPS) in vitro, thus indicating its immune stimulating effects for the cancer-immunosuppressed lymphocytes. Moreover, Isorel inhibited the incorporation of 3H-labelled amino acids (protein synthesis) in various malignant cell lines. For the growth inhibition mostly higher MW components were responsible, although even less than 500 Da components were also active. We further analyzed the effects of drug application in vicinity of tumor (murine mammary carcinoma) and compared it with systemic effects. The animals carried mammary carcinoma in both hind limbs and were also injected with tumor cells i.v. to develop artificial lung metastases. Isorel was applied only at the right side (in the limb distal from the tumor) and caused persistent and almost complete inhibition of the tumor growth for 2/7 animals. Anticancer effects were less pronounced on the contralateral side tumors, although tumor growth rate was transiently reduced for some mice. Histology revealed that Isorel treatment, both at the side of tumor and systemically, increased the incidence of apoptosis and necrosis in the tumors, while reduction of mitosis was noticed only for the tumors in vicinity of the tumor exposed to Isorel. Finally, animals treated with Isorel had, on the average, three times less lung metastases than the controls. Thus, we conclude that both local and systemic effects of the application of Isorel could be of benefit for the tumor-bearing organism resulting in immunomodulation combined with tumor growth inhibition and reduction of metastases. According to the in vitro results, antitumorous effects could be the result not only of the mistletoe lectins and the other high MW factors, but also of the very low MW (< 500 Da) substances that deserve further analyses.
槲寄生（欧洲槲寄生）植物疗法的活性原理可被视为细胞毒性和“生物反应调节”活性（增强宿主抗癌防御能力）的结合，这是由植物凝集素和其他生物相关物质的活性所导致的。我们之前发现，诺维制药有限公司（奥地利波茨察赫）在标准化条件下，采用生物测定验证批次一致性，从新鲜槲寄生全株（planta tota）制备的水提取物Isorel，在实验性辅助癌症治疗中可能具有价值，可提高环磷酰胺化疗的效率。在当前研究中，我们发现Isorel可增强荷瘤小鼠淋巴细胞在体外对有丝分裂原（刀豆蛋白A和脂多糖）的反应性，从而表明其对癌症免疫抑制淋巴细胞具有免疫刺激作用。此外，Isorel抑制了各种恶性细胞系中3H标记氨基酸的掺入（蛋白质合成）。对于生长抑制，主要是分子量较高的成分起作用，尽管分子量小于500 Da的成分也有活性。我们进一步分析了在肿瘤（小鼠乳腺癌）附近应用药物的效果，并将其与全身效果进行比较。动物双侧后肢均患有乳腺癌，并且还通过静脉注射肿瘤细胞以形成人工肺转移。Isorel仅应用于右侧（远离肿瘤的肢体），对2/7的动物肿瘤生长产生了持续且几乎完全的抑制作用。对侧肿瘤的抗癌效果不太明显，尽管部分小鼠的肿瘤生长速率暂时降低。组织学显示，Isorel治疗在肿瘤局部和全身应用时，均增加了肿瘤细胞凋亡和坏死的发生率，而仅在暴露于Isorel的肿瘤附近的肿瘤中观察到有丝分裂减少。最后，接受Isorel治疗的动物平均肺转移灶比对照组少两倍。因此，我们得出结论，应用Isorel的局部和全身效果可能对荷瘤机体有益，可导致免疫调节，同时抑制肿瘤生长并减少转移。根据体外实验结果，抗肿瘤作用可能不仅是槲寄生凝集素和其他高分子量因子的结果，也是分子量极低（<500 Da）物质的结果，这些物质值得进一步分析。
