Abstract
The micronutrient selenium is considered as tumor-protective, inter alia in its function
as part of the selenium-dependent glutathione peroxidase (GPx), which exerts important
antioxidative capacity within the cellular glutathione redox system. Over the last
three decades, special interest has focused in this context on prospective epidemiological
studies as well as on comparative determinations of selenium and the GPx in blood
of cancer patients versus control. Little data has become available in relation to
comparative determinations in tissue. Therefore, in the present study we determined
selenium and the selenium-dependent GPx in blood and tissue of cancer patients versus
control. Patients (n = 100) with a broad spectrum of cancer entities, such as ovarian,
breast, stomach, and colorectal cancers, showed significantly diminished whole blood
selenium compared to controls (n = 103; p < 0.001). At the same time, cancer tissue
from ovary, breast, stomach, and colon/rectum contained higher levels of selenium
than control tissue. The differences were significant for breast (p < 0.001) and colorectal
cancer tissue (p < 0.001). Lower levels of selenium were found in cancer tissues of
the endometrium. In patients with colorectal cancer, GPx activities in plasma
(p < 0.05) and erythrocytes (p < 0.001) were, corresponding to the selenium levels
significantly decreased, whereas activities in cancer tissue increased (p < 0.001).
An increased antioxidative capacity in cancer tissue might be an indicator
for anticancer drug-resistances. The results will be discussed while taking into
account results from other authors, which were investigated on Medline. Further research
on intratumoral characteristics in relation to selenium and the glutathione redox
system may be of particular assistance to practical oncology.
Zusammenfassung
Das Spurenelement Selen gilt als tumorprotektiv, unter anderem in seiner Funktion
als Bestandteil der selenabhängigen Glutathion-Peroxidase (GPx), die wichtige antioxidative
Kapazitäten innerhalb des zellulären Glutathion-Redoxsystem wahrnimmt. Auf diesem
Hintergrund fokussierte sich in den letzten drei Jahrzehnten spezielles Interesse
auf prospektive epidemiologische Studien sowie auf vergleichende Bestimmungen von
Selen und GPx im Blut von Tumorpatienten versus Kontrolle. Gering ist die Datenlage
zu vergleichenden Untersuchungen im Gewebe. Deshalb bestimmten wir in dieser Studie
Selen und die selenabhängige GPx im Blut und Gewebe von Tumorpatienten versus Kontrolle.
Patienten (n = 100) mit einem breiten Spektrum von Tumorentitäten, darunter Ovarial-,
Mamma-, Magen- und kolorektale Karzinome, zeigten signifikant geringere Vollblut-Selenspiegel
im Vergleich zur Kontrolle (n = 103; p < 0,001). Gleichzeitig enthielten Tumorgewebe
von Ovar, Mamma, Magen und Kolon/Rektum höhere Selengehalte als die Kontrolle. Die
Unterschiede waren für Mammakarzinome (p < 0,001) und kolorektale Karzinome (p < 0,001)
signifikant. Geringere Mengen an Selen als die Kontrolle wurde für karzinomatöses
Gewebe des Endometriums gefunden. Korrespondierend zu den Selengehalten zeigten sich
für Patienten mit kolorektalen Karzinomen signifikant erniedrigte GPx-Aktivitäten
im Plasma (p < 0,05) und Erythrozyten (p < 0,001), dagegen erhöhte Aktivitäten im
Tumorgewebe (p < 0,001). Erhöhte antioxidative Kapazitäten im Tumorgewebe stellen
möglicherweise einen Indikator für Zytostatika-Resistenzen dar. Die Ergebnisse werden
unter Berücksichtigung der durch eine Medline-Recherche erhobenen Studienergebnisse
anderer Autoren diskutiert. Weiterführende Untersuchungen intratumoraler Charakteristika
zu Selen und dem Glutathion-Redoxsystem könnten hilfreiche Erkenntnisse für die praktische
Onkologie liefern.
Key words
Selenium - Glutathione peroxidase - Tissue - Blood - Anticancer drug-resistance
Schlüsselwörter:
Selen - Glutathion-Peroxidase - Gewebe - Blut - Zytostatika-Resistenz
References
- 1
Raymann M P.
the importance of selenium to human health.
Lancet.
2000;
356
233-241
- 2
Ursini F, Maiorino M, Brigelius-Flohé R, Aumann K D, Roveri A, Schomburg D, Flohé L.
Diversity of glutathione peroxidases.
Methods Enzymology.
1995;
252
38-53
- 3
Combs G F, Gray W.
Chemopreventive Agents: Selenium.
Pharmacol Ther.
1998;
79
179-192
- 4
Vincenti M, Rovesti S, Bergomi M, Vivoli G.
The epidemiology of selenium and human cancer.
Tumori.
2000;
86
105-118
- 5
Bratakos M S, Vouterakos T P, Ioannou P V.
Selenium status of cancer patients in Greece.
Sci Total Environ.
1990;
92
207-222
- 6
Pawlowic Z, Zachara B A, Trafikowska U, Maciag A, Marchaluk E, Nowicki A.
Blood selenium concentrations and glutathione peroxidase activities in patients with
breast cancer and with advanced gastrointestinal cancer.
J Trace Elem Electrolytes Health Dis.
1991;
5
275-277
- 7
Lund-Pero M, Jeppson B, Pero R W.
Reduced non specific steroidal esterase activity in human malignant tumor tissue from
liver, colon and breast when compared to peritumoral and normal tissue levels.
Anticancer Res.
1994;
14
2747-2753
- 8
Hwang D, Scollard D, Byrne J, Levine E.
Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer.
J Natl Cancer Inst.
1998;
90
455-460
- 9
Balasubramaniyan N, Subramanian S, Govindasamy S.
Status of antioxidant systems in human carcinoma of uterine cervix.
Cancer Lett.
1994;
87
187-192
- 10
Oster O, Schmiedel G, Prellwitz W.
The organ distribution of selenium in German adults.
Biol Trace Elem Res.
1988;
15
23-45
- 11
Hartfiel W, Bahners N.
Selenium deficiency in the Federal Republic of Germany.
Biol Trace Elem Res.
1988;
15
1-12
- 12
Güntzler W A, Kremers H, Flohé L.
An improved couplet test procedure for glutathione peroxidase in blood.
Z Klin Chem Klin Biochem.
1974;
10
444-448
- 13
Oster O, Schmiedel G, Prellwitz W.
Correlations of blood selenium with hematological parameters in West German adults.
Biol Trace Elem Res.
1988;
15
47-52
- 14
Welz B, Melcher M, Neve J.
Determination of selenium in human body fluids by hydride generation atomic absorption
spectroscopy.
Anal Chim Acta.
1984;
165
131-139
- 15
Jendryczko A, Pardela M, Kozlowski A.
Erythrocyte glutathione peroxidase in patients with colon cancer.
Neoplasma.
1993;
40
107-109
- 16
Djuric Z, Malviya V K, Deppe G, Malone J M, McGunagle D L, Heilbrun L K, Reading B A,
Lawrence W D.
Detoxifying enzymes in human ovarian tissues: comparison of normal and tumor tissues
and effects of chemotherapy.
J Cancer Res Clin Oncol.
1990;
116
379-383
- 17
Abou Ghalia A H, Fuoad I M.
Glutathione and its metabolizing enzymes in patients with different benign and malignant
diseases.
Clin biochem.
2000;
33
657-662
- 18
Sharma K, Mittal D K, Kesarwani R C, Kamboj V P, Chowdhery.
Diagnostic and prognostic significance of serum and tissue trace elements in breast
malignancy.
Indian J Med Sci.
1994;
48
227-232
- 19
Rizk S L, Sky-Peck H H.
Comparison between concentrations of trace elements in normal and neoplastic human
breast tissue.
Cancer Res.
1984;
144
5390-5394
- 20
Drake E N, Sky-Peck H H.
Discriminant analysis of trace element distribution in normal and malignant human
tissues.
Cancer Res.
1989;
49
4210-4215
- 21
Borella P, Bargellini A, Caselgrandi E, Piccinini L.
Observations on the use of plasma, hair and tissue to evaluate trace element status
in cancer.
J Trace Elem Med Biol.
1997;
11
162-165
- 22
Di Ilio C, Sacchetta P, Del Boccio G, La Rovere G, Federici G.
Glutathione peroxidase, glutathione S-transferace and gluthatione reductase activities
in normal and neoplastic human breast tissue.
Cancer Lett.
1985;
29
37-42
- 23
Howie A F, Forrester L M, Glancey M J, Schlager J J, Powis G, Beckett G J, Hayes J D,
Wolf C R.
Gluthatione S-transferase and glutathione peroxidase expression in normal and tumor
human tissues.
Carcinogenesis.
1990;
11
451-458
- 24
Iscan M, Coban T, Bulbul D, Eke B C, Aygormez S, Berberoglu U.
Xenobiotic metabolizing and antioxidant enzymes in normal and neoplastic human breast
tissue.
Eur J Drug Metab Pharmacokinet.
1998;
23
497-500
- 25
Perquin M, Oster T, Maul A, Froment N, Untereiner M, Bagrel D.
The glutathione-related detoxification pathway in the human breast: a highly coordinated
system disrupted in the tumour tissues.
Cancer Lett.
2000;
158
7-16
- 26
Punnonen R, Kudo R, Punnonen K, Hietanen E, Kuoppala T, Kainulainen H, Sato K, Ahotupa M.
Activities of antioxidant enzymes and lipid peroxidation in endometrial cancer.
Eur J Cancer.
1993;
29A
266-269
- 27
Ohwade M, Suzuki M, Sato I, Tsukamoto H, Watanabe K.
Glutathione peroxidase activity in endometrium: effects of sex hormones and cancer.
Gynecol Oncol.
1996;
60
277-282
- 28
Burguera J L, Villasamil L M, Burguera M, Carrero P, Rondon C, Matousek A, Brunetto M R,
Gallignani M.
Gastric trissue selenium levels in healthy persons, cancer and non-cancer patients
with different kinds of mucosal damage.
J Trace Elem Med Biol.
1995;
9
160-164
- 29
Wu C W, Wei Y Y, Chi C W, Lui W Y, P'eng F K, Chung C.
Tissue potassium, selenium, and iron levels associated with gastric cancer progression.
Dig Dis Sci.
1996;
41
119-125
- 30
Baur G, Wendel A.
The activity of the peroxide-metabolizing system in human colon carcinoma.
J Cancer Res Clin Oncol.
1980;
97
267-273
- 31
Öztürk H S, Karaayvaz M, Kacmaz M, Kavutcu M, Akgül H, Durak I.
Activities of the enzymes participating in purine and free-readical metabolism in
cancerous human colorectal tissues.
Cancer Biochem Biophys.
1998;
16
157-168
- 32
Siegers C-P, Bose-Younes H, Thies E, Hoppenkamps R, Younes M.
Glutathione and GSH-dependent enzymes in the tumorous and non-tumorous mucosa of the
human colon and rectum.
J Cancer Clin Oncol.
1984;
107
238-241
- 33
Mekhail-Ishak K, Hudson N, Tsao M S, Batist G.
Implications for therapy of drug-metabolizing enzymes in human colon cancer.
Cancer Res.
1989;
49
4866-4869
- 34
Lewis A D, Hayes J D, Wolf R D.
Glutathione and glutathione-dependent enzymes in ovarian adenocarcinoma cell lines
derived from a patient before and after the onset of drug resistance: intrinsic differences
and cell cycle effects.
Carcinogenesis.
1998;
9
1283-1287
- 35
Batist G, Tulpule A, Sinha B K, Katki A G, Myers C E, Xowan K H.
Overexpression of a novel anionic glutathione transferase in multidrug-resistant human
breast cancer cells.
J Biol Chem.
1986;
261
544-549
- 36
Kartner N, Riordan J R, Ling V.
Cell surface p-glycoprotein associated with multidrug resistance in mammalian cell
lines.
Science.
1983;
221
1285-1287
- 37
Thorgeirsson S S, Huber B E, Sorrell S, Fojo A, Pastan I, Gottesman M M.
Expression of the multi-drug resistant gene in hepatogenesis and regenerating rat
liver.
Science.
1987;
236
1120-1122
- 38
Arrick B A, Nathan C F.
Glutathione metabolism as a determinant of the therapeutic efficacy: a review.
Cancer Res.
1984;
33
4224-4232
- 39
Green J A, Vistica D T, Young R C.
Potentiation of melphalan cytotoxicity in human ovarian cancer cell lines by glutathione
depletion.
Cancer Res.
1984;
44
5427-5431
- 40
Hamilton R C, Winkler M A, Louie K G, Batist G, Behrens B C, Tsuruo T, Grotzinger K R,
McKoy W M, Young R C, Ozols R F.
Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant
and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated
glutathione depletion.
Biochem Pharmacol.
1985;
34
2583-2586
- 41
Ohkawa K, Tsukada Y, Dohzono H, Koike K, Terashima Y.
The effects of co-administration of selenium and cis-platin (CDDP) on CDDP-induced
toxicity and antitumour activity.
Br J Cancer.
1988;
58
38-41
- 42
Baldew G S, van den Hamer C JA, Los G, Vermeulen N PE, Goeij J JM, McVie J G.
Selenium-induced protection against cis-diamminedichloroplatinum (II) nephrotoxicity
in mice and rats.
Cancer Res.
1989;
49
3020-3023
- 43
Roth T, Fiebig H-H.
Cytotoxic profile of sodium selenite (selenase®) and sodium selenite in combination
with clinically used chemotherapeutic agents in human tumor models in vitro.
Onkologie.
1999;
2
(2)
30-39
Dr. med. Angeliki Chrissafidou
Kirschallee 6
53115 Bonn
Telefon: + 49-228-261546
Fax: + 49-228-261503