Омела белая Viscum album Mistletoe
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- Methods
- Selection
- Validity assessment and data abstraction
BackgroundBreast and gynaecological cancers (i.e. ovarian, endometrial, cervical, vaginal, vulval, and fallopian cancers) account for a significant amount of morbidity and mortality in women. In Europe an estimated 429,900 cases were diagnosed as breast cancer in 2006 (13.5% of all cancer cases) and 131,900 died from it, despite substantially improved treatment options (surgery, chemotherapy, radiation, hormonal and targeted therapies) [1]. Of female cancer survivors more than half had suffered from breast or gynaecological cancer [2]. 40% to 80% of these patients use complementary therapies additionally to well-established treatments [3-8]. This includes a variety of medicinal plants, but also acupuncture, psychosocial support, yoga, art therapies and others. These are supportive measures to control symptoms, improve quality of life, boost the immune system, and possibly prolong life. Sufficient evaluation is often lacking, however, of the extent to which these therapeutic goals are achieved, as well as of issues relating to safety and mode of action. Medicinal plants in particular have a long history in the treatment of cancer and other conditions connected with tumours, and also play a major role in the development of new drugs today. Over 60% of currently used anti-cancer agents originally derive from natural sources such as plants, marine organisms and micro-organisms [9]. Across Europe, Viscum album L. extracts (VAE or European mistletoe, not to be confused with the Phoradendron species or "American mistletoe") are among the most common herbal extracts applied in cancer treatment [3,7,8,10]. Viscum album is a hemi-parasitic shrub and contains a variety of biologically active compounds. Mistletoe lectins (ML I, II and III) have been most thoroughly investigated. MLs consist of two polypeptide chains: a carbohydrate-binding B-chain that can bind on cell surface receptors, which enables the protein to enter the cell [11-13]; and the catalytic A-chain which can subsequently inhibit protein synthesis, due to its ribosome-inactivating properties, by removing an adenine residue from the 28S RNA of the 60S subunit of the ribosome [11]. Other pharmacologically relevant VAE compounds are viscotoxins and other low molecular proteins, VisalbCBA (Viscum album chitin-binding agglutinin) [14], oligo- and polysaccharids [15,16], flavonoids [17], vesicles [18], triterpene acids [19], and others [20,21]. Whole VAE as well as several of the compounds are cytotoxic and the MLs in particular have strong apoptosis-inducing effects [22-24]. MLs also display cytotoxic effects on multidrug-resistant cancer cells (e.g. MDR+ colon cancer cells [25]) and enhance cytotoxicity of anticancer drugs [26,27]. In mononuclear cells VAE also possess DNA-stabilizing properties. VAE and its compounds stimulate the immune system (in vivo and in vitro activation of monocytes/macrophages, granulocytes, natural killer (NK) cells, T-cells, dendritic cells, induction of a variety of cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, GM-CSF, TNF-α, IFN-γ (overview see [20,21]). The cytotoxicity of human natural and lymphokine-activated killer cells, for instance, can be markedly enhanced in vitro by VAE rhamnogalacturonans, which bridge these killer cells with NK-sensitive or insensitive tumour cells [28,29]. Furthermore, VAE seem to interfere with tumoural angiogenesis [30,31]. Injected into tumour-bearing animals, VAE and several of their compounds (MLs, a 5 kDa protein not specified further, protein complexes isolated by Vester and colleagues, oligosaccharids) display growth-inhibiting and tumour-reducing effects [20,21]. Despite extensive experimental analyses of their biological properties, many questions regarding the precise mode of action of VAE still remain. For clinical application VAE are made from mistletoes grown on different host trees [Host trees of VAE: Fir (Abies, A); maple (Acer, Ac); almond tree (Amygdalus, Am); birch (Betula, B); whitethorn (Crataegus, C); ash tree (Fraxinus, F); appletree (Malus, M); pine (Pinus, P); poplar (Populus, Po); oak (Quercus, Qu); willow (Salix, S); lime (Tilia, T), elm (Ulmus, U)], either by aqueous extraction, partly combined with fermentation, or by pressing procedures. Depending on host tree, harvesting time and extraction procedure, VAE vary in regard to their active compounds and biological properties. Different commercial VAE preparations are available, and a recombinant ML (rML) drug is currently being developed and tested in clinical trials [32,33]. Clinical effects of VAE in cancer have been investigated in a variety of studies and assessed in systematic reviews [34-39]. These reviews, however, had inconsistent results, they are outdated, incomplete or concentrate on partial aspects. No review has yet assessed clinical and preclinical effects specifically and comprehensively for breast and gynaecological cancer, although there is widespread usage in these patients [3,7]. Our primary aim was therefore to assess the potential therapeutic effectiveness of VAE, and their potential biological effects on breast and gynaecological cancer in clinical and preclinical studies.
MethodsDesignSystematic review of clinical and preclinical studies investigating the influence of VAE on breast or gynaecological cancer. Search strategyWe used a systematic process to search the following databases for clinical trials – AMED, Biosis Previews, Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, The NHS Economic Evaluation Database, Health Technology Assessment Database), Embase, Medline/Premedline, NLM Gateway, private databases – from inception of these databases to December 2008 using the terms (MISTLETOE OR VISCUM? OR MISTEL? OR ISCADOR? OR ISCAR OR HELIXOR OR ABNOBA? OR ISCUCIN OR ISOREL OR VISOREL OR ?SOREL OR WELEDA OR WALA OR EURIXOR OR LEKTINOL OR PLENOSOL OR AVISCUMINE) AND (STUDY? OR STUDIE? OR TRIAL OR EVALUAT? OR RANDOM? OR INVESTIG? OR COHORT? OR KOHORT? OR OUTCOME?). The reference list from each potentially eligible study, relevant review article and textbook was checked, and experts in the field and manufacturers of mistletoe preparations were contacted for additional reports. Regarding in vitro or in vivo (animal) experiments on anticancer effects, we checked title and abstract, and, where necessary, the whole article of each VAE-related reference in the databases (Medline/Pubmed and comprehensive private databases, using above mentioned terms but without restriction to clinical studies) and in major surveys. SelectionThe following selection criteria were used for inclusion of studies in the analysis: (I) prospective randomized or non-randomized controlled clinical trial, or prospective single-arm cohort study (e.g. phase II trial) or pharmaco-epidemiological cohort study; (II) study population with breast or gynaecological cancer, i.e. ovary, uterus, cervix, genital cancer, or cervical intraepithelial neoplasm (CIN); (III) intervention group treated with VAE preparation; (IV) clinically relevant outcome (i.e. survival, disease-free interval, remission, relapse, QoL, or reduction of side effects or immune suppression during cytoreductive therapy); (V) completion of study; (VI) published or unpublished. Studies were excluded if they: only measured toxicity or tolerability (phase I trial), only measured stimulation of immunological parameters, were not conducted on cancer patients, or had a retrospective design (except pharmaco-epidemiological cohort studies). There were no restrictions on language. For in vitro and animal experiments the criteria were adapted accordingly; unpublished material was not included however. In vitro experiments were restricted to cancer cells originating from human tumours. Validity assessment and data abstractionCriteria-based analysis was performed on the selected clinical studies to assess their methodological quality. Analyses were performed independently by two reviewers (GK, HK). There were no major differences in study assessment; disagreements were resolved by discussion. Criteria for assessing strength of evidence in controlled trials were adapted from the National Health Service Centre for Reviews and Dissemination [40] and from criteria for good methodology as already applied in earlier reviews on VAE trials [34,36,41]. Quality criteria were adjusted for cohort studies [36]. Data were abstracted by one reviewer (GK) and checked by a second reviewer (AG). When necessary, primary authors of the trials were contacted for additional information. Regarding animal experiments we extracted data on study size, animal model, tumour type, tumour transfer, intervention, treatment schedule, outcome, physiological monitoring, side effects, dose-response, randomization, control treatment, blinding of outcome assessment, publication in a peer-reviewed journal, and funding source. |