An overview on anticancer activities of the Viscum album extract Isorel.
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.
Zarkovic
N
N
Rudjer Boskovic Institute, Division of Molecular Medicine, HR-1000 Zagreb, Croatia. zarkovic@rudjer.irb.hr
Vukovic
T
T
Loncaric
I
I
Miletic
M
M
Zarkovic
K
K
Borovic
S
S
Cipak
A
A
Sabolovic
S
S
Konitzer
M
M
Mang
S
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D037121:Plant Lectins; D010946:Plants, Medicinal / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000972:Antineoplastic Agents, Phytogenic; C049374:Isorel M; D008070:Lipopolysaccharides; D010936:Plant Extracts; D037121:Plant Lectins; D003208:Concanavalin A