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Phytomedicine 18S (2011) S3–S6

Contents lists available at SciVerse ScienceDirect

Phytomedicine

journa l homepage: www.e lsev ier .de /phymed

istletoe in Tumour Therapy Basic Research and Clinical Practice0–12 November 2011 Nonnweiler-Otzenhausen, Germany

ectins – Potential sources and potential benefits

olfgang Kreis ∗

Lehrstuhl für Pharmazeutische Biologie, Friedrich-Alexander Univer-ität Erlangen-Nürnberg, Staudtstr. 5, D-91058 Erlangen; Erlangenenter of Plant Science (ECROPS), Germany

Tel.: +49 9131 8528241; fax: +49 9131 8528243.-mail address: wkreis@biologie.uni-erlangen.de.

Introduction: The term lectin was introduced by William Boydn 1954 and used to characterize proteins with an ability to bindarbohydrates. Lectins can be classified on the basis of their carbo-ydrate specificity or – depending on their overall structures – theyan be categorized into merolectins, holoectins, chimerolectins anduperlectins. Their biological activity can also be used for classifi-ation. For example, type 2 ribosome-inactivating proteins (RIPs)rigger the catalytic inactivation of ribosomes. The most known

embers of this family are ricin and the mistletoe lectins. It is well-ccepted that mistletoe lectin (ML I) can be used in cancer patientso improve the quality of life. One may ask whether this is a specificeature of ML I or whether other plant lectins could be used in a sim-lar or even more specific way since other plant species contain RIPsdubbed type 2) lacking the tremendous unspecific toxicity of, e.g.icin. Especially these non-toxic type 2 RIPs are promising tools forancer therapy. This review is intended to provide an overview overotential sources of lectins, their production and their potentialpplication.

Sources of lectins: Lectins are found in a diversity of organisms,mportant sources being plants. In contrast to other organisms, sev-ral plants produce and accumulate quite high amounts of lectins.ectins may accumulate in roots and tubers (Astragalus, Remusa-ia, Phytolacca) or in fruits and seeds (Hibiscus, Phaseolus, Ricinus).specially legumes are a rich source of lectins.

Production of lectins: Lectins with specific carbohydrate speci-city have been purified from various plant tissues and otherrganisms. It has to be taken into consideration that specific lectinsf low abundance but utmost interest can nowadays be producedy recombinant techniques using E. coli cells transformed with anppropriate expression vector containing the cDNA or gene that

ncodes the sequence of the target lectin.

Potential application of lectins: Lectins have a large diversityf exciting biological activities including antifungal, anti-tumour,IV-1 reverse transcriptase inhibitory and immunomodulatory

944-7113/$ – see front matteroi:10.1016/j.phymed.2011.09.001

activities, which may find clinical applications. In this review spe-cial emphasis is placed on the anti-cancer activities. For example,lectins can elicit apoptosis in different cancer cell lines. Amongthe examples studied are Sophora flavescens lectin (HeLa cells),Polygonatum odoratum lectin (Fibrosarcoma cells) and Polygonatumcyrtonema lectin (Human melanoma cells).

Keywords: Cancer; Lectin; Recombinant technology; RIP

doi:10.1016/j.phymed.2011.09.002

Mistletoe lectins as biologically active substances in aqueousmistletoe extracts

U. Pfüller ∗, U. Schumacher

Institute for Anatomy and Experimental Morphology, Center for Exper-imental Medicine, University Medical Center Hamburg Eppendorf,Martinistrasse 52, 20246 Hamburg, Germany

∗ Corresponding author. Tel.: +49 040 741052586/030 6744120;fax: +49 040 741055427.E-mail address: upfuelle@uke-uni-hamburg.de (U. Pfüller).

Aqueous mistletoe extracts contain a large variety of poten-tially therapeutically active substances, which are altogetherresponsible for the wide range of physiological effects seen aftermistletoe application. However, a broad body of evidence now sug-gests that the main biologically active substances responsible forimmunomodulatory and cytotoxic effects are represented by thethree mistletoe lectins (MLs).

While crystallography has revealed the molecular structure ofML-I and -III, ML-II has not as yet been investigated by X-raycrystallography. Data on the galactosyl/N-acetylgalactosyl targetstructures (glycoproteins) will be presented including studies onthe modification of glactosyl residues by sialic acid and the bindingpattern observed of these two lectins towards the modified glyco-proteins. MLs do not only bind to carbohydrates but also to peptidestructures which act as glycomimetics. Therefore studies on thebinding of ML-I to peptide sequences of the multi drug relatedprotein 5 will be presented. Furthermore, binding of ML-I to neu-raminic acid containing glycolipids like alpha2,6 sialylated neolacto

gangliosides will be discussed. The latest data on the blocking of thecarbohydrate recognising domain of MLs by synthetic glycoana-logues will be presented. These novel blocking substances havebeen tested on lectins for the first time.

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In addition to the three MLs, a fourth chitin binding lectinVisalbCBA) with specificity for oligomeric N-acetylglucosamineas been described. This lectin belongs to a different gene familyhan the three “classical” MLs.

The biological properties of the MLs, their bioavailability, andheir stability are influenced by further components of the mistle-oe extracts which include amphiphilic viscotoxins, VisalbCBA andolysaccharides. The immunomodulatory and cytotxic effects ofhe MLs will discussed within the context of their potential bindingartners.

Keywords: Mistletoe; Mistletoe lectins; Molecular structure;ugar specificities; Cytotoxicity; Immuno modulation

oi:10.1016/j.phymed.2011.09.003

he role of inflammation in the pathogenesis of cancer

einhild Klein ∗

Department of Internal Medicine II, University of Tübingen, Germany

Tel.: +49 7071 2984479; fax: +49 7071 292760.-mail address: reinhild.klein@med.uni-tuebingen.de.

Chronic inflammation plays a critical role in tumorigenesis.hus, the persistence of several toxic influences (i.e. cigarette smok-ng, exposure to asbestos and silica, etc.), viral (i.e. Hepatitis B or C,IV, Papilloma viruses etc.) or bacterial infections (i.e. Helicobacterylori, Mycobacterium tuberculosis, etc.) or parasites (i.e. Schisto-oma etc.) leading to a chronic inflammation have been shown toe accompanied by an increased risk for the development of cancer.

n contrast, acute inflammatory processes may be rather beneficialith respect to the destruction of already existing tumors.

The immune system consists of two major components, thennate as well as the adaptive immune system. Innate immu-ity senses the presence of foreign entities derived from either

nfections or tissue damage and confers protection by activelynducing inflammatory, anti-microbial and anti-stress responses. Itlso primes the adaptive immune system in case the insult persists.enetic mutations in the innate immune system that alter the equi-

ibrium result in enhanced carcinogenesis. The adaptive immuneystem consists of the cellular and the humoral immune system. Theellular response provides rather anti-angiogenic and proapoptoticffects, a dominance of the humoral immune response has beenegarded as favourable for tumor progression – although also thepposite has been observed. In cancers developing in the setting ofchronic inflammatory process there is not only an overall upreg-lation of immune responses but a shift in the immune responseo one that is characterized by a wound healing, proangiogenic,nti-apoptotic immune response pattern. As the malignant pro-ess develops, cancer cells evolve to subvert the cellular immuneesponse. An acute inflammatory process in such a setting may thene even beneficial due to the activation of the innate immune sys-em, especially of neutrophils and natural killer (NK) cells attackingumor cells. Treatment with substances leading to acute inflam-

ation and activating neutrophils or NK cells, such as mistletoextracts, may, therefore, help to break tolerance to tumor antigensnd improve the destruction and elimination of tumor cells.

All these processes are, however, rather unique for each tumorntity. Continued refinements in our understanding of the complexnterplay between different components of the host response inancer development are, therefore, vital to identify potential newreatment approaches for these devastating diseases.

Keywords: Chronic inflammation; Cancerogenesis; Cellularmmune system; Humoral immune system; Immune homeostasis

oi:10.1016/j.phymed.2011.09.004

18S (2011) S3–S6

Molecular approaches for individualized tumor therapy withstandard drugs, phytochemicals, and medicinal herbs

Thomas Efferth ∗

Department of Pharmaceutical Biology, Institute of Pharmacy and Bio-chemistry, Johannes Gutenberg University, Mainz, Germany∗ Tel.: +49 6131 3925751; fax: +49 6131 3923752.E-mail address: efferth@uni-mainz.de.

Assays to predict the response of tumors towards chemotherapyare relevant for custum-tailored, individualized therapies. Clin-ically, chemotherapy is frequently followed by drug resistance(Gillet et al., 2004). Since most established cytostatic drugs lack suf-ficient tumor specificity, normal tissues are also affected by severeside effects. Novel strategies to broaden the narrow therapeuticrange by separating the effective dose and toxic dose would be ofgreat benefit for the patients.

Whereas the statistical probability of therapeutic success iswell-known for larger groups of patients from clinical therapy tri-als, it is, however, not possible to predict how an individual tumorwill respond to therapy (Volm et al., 2002). Although clinicopatho-logical factors (tumor size, lymph node and far distance metastases)are of prognostic relevance for larger cohorts, they are less helpfulpredicting treatment success or side effects in individual patients.Therefore, efforts have been undertaken to predict drug responsein vitro (Efferth et al., 2008). The idea is to determine sensitiv-ity or resistance beforehand to subsequently choose the clinicallymost effective treatment for each individual patient. The advent ofmolecular biology paved the way for the genetic characterization ofdrug-resistant tumors. Still, the transfer of these techniques fromthe bench to the bed is an unfulfilled requirement. Nevertheless,current progress gives reason to believe that molecular approacheswill significantly improve individual tumor therapy.

We present experiences with predicitive chemosensitivity test-ing of the past two decades. We span a bow from relevantcytotoxicity assays, immunohistochemical detection of prognos-tic markers for therapy response of tumors and survival time ofpatients to modern pharmacogenomic techniques (comparativegenomic hybridization, DNA methylation arrays, mRNA and micro-RNA expression arrays, etc.) (Efferth, 2010). Own data obtained bythese methods will be compared to clinical data of patients. Wewill present results for the prediction of sensitivity and resistanceboth to classical anticancer drugs as well as to phytochemicals andmedicinal herbs (Li et al., 2008). The presented techniques alsopossess relevance for phytotherapeutic drugs such as mistletoepreparations, which are already well established in clinical routinetherapy.

Keywords: Drug resistance; Genetics; Microarrays; Personal-ized medicine; Pharmacogenomics; Pharmacognosy; Phytother-apy; Prognostic factor; Survival time

References

Gillet, J.P., Efferth, T., Steinbach, D., Hamels, J., de Longueville, F., Bertholet, V.,Remacle, J., 2004. Microarray-based detection of multidrug resistance in humantumor cells by expression profiling of ATP-binding cassette transporter genes.Cancer Res. 64, 8987–8993.

Volm, M., Koomägi, R., Mattern, J., Efferth, T., 2002. Expression profile of genes innon-small cell lung carcinomas from long-term surviving patients. Clin. CancerRes. 8, 1843–1848.

Efferth, T., Konkimalla, V.B., Wang, Y.F., Sauerbrey, A., Meinhardt, S., Zintl, F., Mattern,J., Volm, M., 2008. Prediction of broad spectrum resistance of tumors towardsanticancer drugs. Clin. Cancer Res. 14, 2405–2412.

Efferth, T., 2010. Personalized cancer medicine: from molecular diagnostics to tar-geted therapy with natural products. Planta Med. 76, 1143–1154.

Li, P.C., Lam, E., Roos, W.P., Zdzienicka, M.Z., Kaina, B., Efferth, T., 2008. Artesunatederived from traditional Chinese medicine induces DNA damage and repair.Cancer Res. 68, 4347–4351.

doi:10.1016/j.phymed.2011.09.005