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Can thiocyanate and thiocyanate precursors from Brassica species support the tumor therapy? W.-D. Jülich, U. Lindequist Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst- Moritz- Arndt- University Greifswald F.-L.- Jahn -Straße 15, 17487 Greifswald, Germany Conclusions Thiocyanates activate the metabolism of cells. This effect together with the well known immune stimulating effect could support prophylaxis and therapy of cancer diseases. After a vegetable rich nutrition with a high glucosinolate or thiocyanate content the thiocyanate level in the blood is increased. Although this increase is only small in comparison to the strong increase of thiocyanate level in tumor patients the demonstrated cellular effects let expect considerable benefit for the patient. Possible interactions with the tumor therapy have to be observed carefully. Introduction Cancer prevention by food is well investigated and supported by many authors. It was shown that an extract of broccoli sprouts (Brassica oleracea, convar. botrytis, var. italica) is a highly promising substance for bladder cancer prevention. During urinary excretion the compounds from the extract are selectively delivered to the bladder epithelium [1]. Also Sauerkraut, which is prepared from slightly fermented cabbage, exhibits in animal studies a promising tumor inhibiting potential [2]. Brassicaceae are especially rich in glucosinolates (“organic thiocyanates”) [3]. Besides glucosinolates, the plants contain enzymes, which are able to break down the glucosinolates mainly into isothiocyanates and thiocyanates (“anorganic thiocyanate” SCN-) [4]. Therefore Brassica spec. contain high amounts of SCN(Tab. 1). To complete the cancer prevention, anorganic thiocyanate is therefore of special interest. Tab. 1: SCN- content of Brassica spec.[5] Brassica spec. Var. SCNµmol/kg B. oleracea L. var. capitata con. var. alba con. var. rubra var. botrytis var. sabouda var. gemnifera 334-1500 400-800 500-2000 1300-2170 217-2500 var. gongylodes var. rapa 350-700 1500-2500 B. rapa L. Serum thiocyanate level of humans Normal conditions Brassica rich nutrition 60-70 % of the SCN--pool is endogen produced. Under normal nutrition conditions people take up about 50 µmol SCN´- per day. This together with the endogen produced amount results in a serum thiocyanate level of about 50-70 µmol/l. Tumor patients Tumors of The thiocyanate level of patients with malignant tumors is much higher than those in health people [6]. In average the SCN--level is about two times higher than in the controls (Table 2). This can be evaluated as sign of an increased activity of the immune system of the patient. n Sceleton system Gastrointestinal system Mamma Female genital system Thoracic cavity Skin Controls A nutrition with a high Brassica content could support the SCN--uptake. The thiocyanate level in serum is increased after brassica rich nutrition by about 1-10 µmol/l [7]. 13 µmol SCN-/l 175+78 68 25 39 60 89 294 150+68 147+92 139+47 125+53 100+7 63+41 Influence of an increased thiocyanate level on cell metabolism Methods Results We have investigated the influence of SCN- on the metabolism of human cells (FL-cells). An essential precondition to control the metabolism of cells over longer times is to realize their survival under in vivo like conditions. These conditions can be realized in a perfused cell culture [8]. Fresh nutrition medium is supplied and metabolic products are removed continuously. During 12 days a very stable glucose consumption as parameter for cell metabolism and vitality can be measured. The metabolism of the cells is activated. The glucose consumption is significantly (Friedman-test) increased. The cells are more stable against stress. -50 -60 guinea pig, female mice, female N SC clo ph osp ha mid + -40 Cy N -30 clo ph osp ha mid -20 tro l -10 Cy But in another animal model, the teratogenic effects of procarbazins on Os metacarpale III, Ossa digitalia III and V and the Fibula are increased by application of SCN- [10]. 0 SC This side effect of a tumor chemotherapy with cyclophosphamid is decreased by application of SCN- in an animal model [9]. 10 con The number of leucocytes is decreased during the treatment with cyclophosphamid. number of leucocytes (%) Influence of SCN- on side effects of tumor therapy guinea pig, male mice, male References: [1] R. Munday, P.Mhawech-Fauceglia, Ch. M. Munday, J.D. Paonessa, L Tang, J. S. Munday, C. Lister, P Wilson, J. W. Fahey, W. Davis and Y. Zhang: Inhibition of Urinary Bladder Carcinogenesis by Broccoli Sprouts. Cancer Res. 68, 1593–600 (2008). [2] E.-L. Ryhanen: J.Agric. Food Chem 50, 6798-6803 (2002). [3] M.E. Daxenbichler, C.H. Vanstetten, P.H. Williams.: Glucosinolate Products in Commercial Sauerkraut. J. Agric. Food Chem. 28, 809-811 (1980). [4] J.W. Fahey, Y. Zhang, P.Talalay.: Broccoli spouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl. Acad. Sci. USA 94, 10367-10372 (1997). [5] W. Weuffen, H. Decker: Thiocyanat –ein bioaktives Ion. IS.M.H. Verlag Törpin 2004. [6] W.-D. Jülich, W. Weuffen, H.-L. Jenssen und H. Köhler: Beziehungen zwischen den Ergebnissen des Makrophagen-Elektrophorese-Mobilitäts-Tests und dem Rhodanidspiegel bei Patienten mit malignen Tumoren, Autoaggressionskrankheiten und nach Transplantation. Acta biol. med. german. 34, 1541 – 1547 (1975). [7] W,.D.Jülich, A. Kramer, V. Hingst, H.-G. Sonntag, C, Schütt, M. Daut, A. Schulz, G. Bahlmann, H. Zöllner, R. Hampel, E. Panzig: Untersuchungen zur Stimulierung der Immunantwort bei der Hepatitis-B-Schutzimpfung durch eine alimentäre Thiocyanatsupplementierung bei gesunden Probanden und bei Dialysepatienten. Umweltmed. Forsch. Prax 2, 71-83 (1997). [8] T h. v.Woedtke, U. Lindequist, N. Alhitari, C. Kusnick, W.-D. Jülich, P. Abel: The usefulness of a biosensor controlled perfusion cell culture for the investigation of new drugs demonstrated with the marine fungus Kirschsteinothelia maritima. Pharmazie 57 (4)270 (2002) [9] A. Kramer, M. Kühn, W.-D. Jülich: Verminderung der durch Cyclophosphamid induzierten Leukopoesesuppression durch Thiocyanat. Hyg. Med. 21, 34 (1996). [10]S.Liefländer: Zum Einfluss von Folsäure und Thiozyanat auf die Knochenreifung der LEW.1A-Ratte unter Procarbazinapplikation in zytostatischer Dosierung. Diss. Med. Fak. Univ. Greifswald 2006