Role of Trace Elements in Cancer'

[CANCER RESEARCH35,3481-3487,Novcmbcr1975] Role of Trace Elements in Cancer'

Morton K. Schwartz

Department of Biochemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Summary jurious effects of hydrogen peroxide; and vanadium blocks cholesterol biosynthesis. The review considers trace elements including fluorine, In animal deficiency studies it has been determined that copper, manganese, zinc, cobalt, chromium, selenium, selenium can prevent muscular dystrophy and liver necrosis molybdenum, tin, vanadium, silicon, and nickel from the in rats and white muscle disease in cattle. Chromium is standpoint of their role as either inhibitory or causative needed for growth of rats and its deficiency leads to a agents of cancer and also the possible use of their assay in reduced life-span, corneal lesions, and interference with biological fluids as diagnostic or prognostic aids in patients insulin action producing a diabetic state with removal of with cancer. glucose from the blood at a rate that is one-half that of animals on a chromium-containing diet. In other animal deprivation studies the growth of rats was only two-thirds Introduction that of control animals if the diet contained less than I to 2 ppm of tin or less than 0. 1 ppm of vanadium. Fluoride is essential for growth of rats, silicon is needed for the The role of trace metals in cancer has been the subject of development of skeleton and feathers of young chicks, and conjecture, and reports of different authors are often nickel is essential for the growth of wing and tail feathers conflicting and contradictory. A major reason for these (20). discrepancies is the difficulty in analyzing trace elements The effects of trace elements are related to concentration and the problems that exist in collecting specimens without and recorded observations range from a deficiency state, to contamination (82). Trace elements are required in small function as biologically essential components, to an unbal concentrations as essential components of biological en ance when excess of one element interferes with the function zyme systems or of structural portions of biologically active of another, to pharmacologically active concentrations (i.e., constituents. They constitute, in toto, less than 0.01 % by zinc in healing), and finally to toxic and even life-threaten weight of the total body composition and those thus far ing concentrations (85). The purpose of this review is to defined as essential in animal deficiency experiments include consider the trace elements from the standpoint of both iron, iodine, fluorine, copper, manganese, zinc, cobalt, their role in carcinogenesis and the possible use of their chromium, selenium, molybdenum, tin, vanadium, and assay in biological fluids as diagnostic or prognostic aids possibly silicon and nickel (20). The metals (all of the above in patients with cancer. Iron and iodide will not be except idodine, fluorine, and selenium) play their most considered since they have been the subject of many reviews important role as cofactors in enzymes. Iron is an important and, although present in relatively small concentrations, constituent of succinate dehydrogenase as well as a part of they are psychologically, if not physiologically, not â€œtrace the heme of hemoglobin, myoglobin, and the cytochromes. elements. â€œThe review will not consider such elements as Zinc is involved in carbonic acid (carbonic anhydrase), and arsenic or mercury that have been shown to be cancerigenic, in alcohol (alcohol dehydrogenase) formation, and in pro but are not essential for animal growth (21, 51, 89). teolysis (carboxypeptidase, leucine aminopeptidase, etc.) (4). Copper is present in many enzymes involved in oxida Zinc tion (tyrosinase, ceruloplasmin, amine oxidase, cytochrome oxidase), and manganeseis a part of enzymesinvolved in Reports of zinc values in biological fluids of cancer urea formation, pyruvate metabolism, and the galacto patients have been variable. Serum yields higher zinc levels transferase of connective tissue biosynthesis. In addition to than does plasma, presumably due to platelet breakdown. its role in vitamin 12,cobalt is also a cofactor of enzymes There is a diurnal variation in serum zinc concentrations, involved in DNA biosynthesis and amino acid metabolism. and zinc values less than the fasting concentrations are Molybdenum plays an important role in purine metabo observed for 2 to 3 hr after the ingestion of food. In addition lism; selenium is related to glutathione peroxidase, an en there is a decline in zinc levels with increasing age and zyme involved in the protection of hemoglobin against in women demonstrate lower levels than men (5). Normal RBC contain about 10 times the concentration of zinc seen

1 Presented at the conference on Nutrition in the Causation of Cancer, in serum, and about 30%ofserum zinc is bound to albumin. May 19 to 22, 1975, Key Biscayne, Fla. This review was supported in part Zinc is presumably transported bound to a specific a2- by USPHS Grant CA 08748from the National Cancer Institute. glycoprotein (22). Because of the possible variables in serum

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1975 American Association for Cancer Research. M. K. Schwartz zinc levels, it has been suggested that RBC zinc concentra related to cancer of the esophagus and stomach (44, 71). tions may be a better indicator of zinc deficiency states. Poswillo and Cohen (60) found that ingestion of zinc Low serum zinc levels have been observed in serum of inhibited the development of tumors. It has been reported patients with cancer of the bronchus and colon, but not in that a dietary deficiency of zinc inhibits the growth of other forms of cancer (9), and in RBC, leukocytes, and Walker 256 carcinosarcoma (I 3, 45) and Lewis lung granulocytes of such patients (37, 76, 86). â€œHypozincemiaâ€•carcinoma (12). Survival of mice with transplanted leu is a nonspecific observation and decreased serum zinc levels kemia or an ascites carcinoma was also prolonged by the have been found in cirrhosis, hepatitis (88), lung infections deficiency (I 2). These effects were attributed to a zinc including tuberculosis, myocardial infarction, renal insuffi deficiency interfering wuth DNA synthesis (65). Guthrie ciency, diseases producing increased muscle metabolism, and Guthrie (22) found that injection of 0.05 ml of 4% zinc acute tissue injury (41, 82), and pregnant women (61). chloride into the testes of Syrian hamsters produced embry Steroid therapy, including administration of p.o. contra onal carcinomas (testicular teratoma) in 2 of 49 animals. ceptives, also produces a hypozincemia (18, 19). Zinc metal powder injected into the trachea and pleura of Patients with cancer excrete as much as 3 times more zinc rats produced reticulosarcomas in the lungs and seminomas in their urine than do normal persons and in such patients in the testicles in 15% of the animals (17). the molybdenum excretion is decreased. Pfeilsticher (56) An important consideration for the cancer patient is the suggested that a ratio of urinary zinc to molybdenum of observation that there is delayed healing in patients with > 300 is indicative of advanced cancer. Zinc levels are lower zinc deficiency (28) and zinc, when administered p.o. to in prostatic cancer tissue than in normal prostate tissue, but postoperative patients, greatly accelerates healing (25, they are increased in benign prostatic hypertrophy tissue 57â€”59).Zinc sulfate p.o. increased the healing rate of bed (23). Liver, kidney, or lung harboring metastasis has a sores and leg ulcers when the serum zinc concentration higher zinc content than does the corresponding normal before treatment was 110 zg/ 100 ml but not in patients with tissue or the tumor itself (34, 90). The liver of patients with greater serum levels (61). This has been attributed to the acute viral hepatitis contains less zinc than does normal liver role of zinc in protein synthesis and collagen formation. and is accompanied by increased zinc in the urine but Zinc, by virtue of its presence in RNA and DNA polymer normal levels in serum. ase, may account for reports of its role in regeneration of rat Kew and Mallett (36) reported that in normal liver tissue liver (62). the zinc concentration is about 78 Â±41 @g/g,wet weight; The exact role of zinc is unknown. Zinc binding may be that of noncirrhotic liver tissue from patients with primary related to cancerigenesis in the sense that the metals may liver cancer is about 75 Â±31 @ig/g;cirrhotic liver tissue from effect catabolic or anabolic enzymes. Chvapil (6) has these patients is about 45 Â±23 zg/g, and the primary liver proposed that zinc is an integral part ofbiomembranes, may cancer itself is about I 8 Â±7 @.tg/g.Lowzinc levels have been control membrane integrity, and may be involved in the reported in hepatic metastases from a variety of sources stability of membranes and in lipid peroxidation-related with greater than normal values in the liver harboring the injury. Zinc has been observed to function as a mitogen cancer. Olson et a!. (54) reported increased liver zinc inducing blastogen transformation of lymphocytes in a concentrations in patients with cancer, and McBean et a!. fashion similar to that of phytohemagglutinin. Phytohemag (43) found increased liver and kidney zinc in patients with glutinin effects are also greater in lymphocytes harvested bronchogenic, gastric, and nasopharyngeal cancer. Liver from rats that had been given a high zinc diet. The role of zinc concentrations of patients dying from noncancerous zinc in RNA and DNA polymerase, its inhibitory effects on disease have been reported to be similar to that of individu phosphodiesterase, and its activating effect on membrane als dying in accidents (43). bound adenyl cyclase, suggest a role for zinc in cancerigene It has been reported that cancerous lung and breast tissue sis. Zinc also has been shown to stabilize ribosomes and the have a higher zinc concentration than does normal tissue DNA double helix. The zinc content of DNA and RNA, (49). In I study the mean zinc concentration ofbreast cancer isolated from Walker 256 carcinosarcoma and sarcoma M. tissue was 5.7 times that of normal breast tissue. The values I, was greater than that in these nucleic acids isolated from in various patients were extremely variable (66). For livers of normal rats. Andronikashvili et a!. (2) found that in example in one patient the tumor had 490zg/g oftissue and DNA and RNA purified from sarcomas the zinc concentra normal tissue 240 @g/g,whereas in a specimen from an tion remained constant following transplantation, but the other patient the zinc concentration was 2.2 jsg/g in the iron, antimony, chromium, cobalt, and selenium decreased. normal tissue and 1.8 @sg/gin the tumor. An increased up It was concluded that the zinc was a necessary part of the take of 5Zn has been found in mammary tumors of mice growth process but that the other elements were not. (84). In bones from normal individuals (human tibia) and in osteogenic sarcoma tissue, a significant difference in Copper zinc concentration was observed (33). In 40 control speci mens the value was 147. 1 Â±49.8 .tg/g, dry weight, com Copper is primarily found in serum (95%) as part of the pared to 465.8 Â± 578.6 jzg/g in 8 osteogenic sarcoma oxidative enzyme ceruloplasmin, an a2-glycoprotein with a specimens. molecular weight of about 150,000. The remainder is The role of zinc as a carcinogenic agent is still subject to present in an ionic form loosely bound to albumin. The daily controversy. Excessive intake p.o. has been reported to be adult requirement is about 2 mg/day and the majority of the

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ingested copper is rapidly converted in the liver to cerulo response to radiotherapy (79). In Hodgkin's disease serum plasmin. Cellular copper is primarily found in mitochon copper determinations are useful indicators of the effec dna, and the adult body contains about 100 to 150 mg with tiveness of chemotherapeutic regimens used in obtaining the highest organ concentration in liver, kidney, heart, the 1st treatment response and then as an early indicator brain, and pancreas. Only 10to 60 zg of copper are excreted of reactivation of disease. Elevations may occur 1 to 6 in the urine each day. months before clinical evidence of relapse has occurred The role of copper, hypocupremia, and elevated liver (28). Similar serum copper levels have been observed in copper concentrations in Wilson's disease are well docu children with Hodgkin's disease (81). mented and the effects of copper toxicity have been clearly In patients with leukemia, normal values were observed in described. Deficiency states have been reported in malab 12 pediatric patients with acute lymphocytic leukemia who sorption (kwashiorkor, sprue, celiac disease), marasmic were in complete remission. In 8 patients with active infants, infants with Mentes kinky hair syndrome, and disease, increased percentages of bone marrow blast cells nephrotic syndrome. Elevations of serum copper have been were associated with abnormal serum copper concentrations reported in multiple sclerosis, infection, myocardial infarc (78, 80). Similar observations were made in 265 pediatric tion, acute and chronic liver disease, and schizophrenia (74). and 89 adult patients with acute lymphatic leukemia (29). There is a relationship between serum copper and inflam The development of tumors in mice after administration of mation, and in some patients, but not all, there is a direct Maloney murine rhabdomyosarcoma virus is preceded by correlation with C-reactive protein. In patients with lym an increase in serum copper as is the induction of reticulum phomatous diseases the role of copper has been the subject cell sarcoma-like lesions in marmosets by Herpes saimiri, or of considerable investigation (32, 48). Elevated serum the growth of Morris hepatoma after s.c. implantation in copper has also been reported following administration of rats (46). estrogens or thyroid and pituitary hormones and after Serum copper has also been found elevated in other forms surgery (31). of cancer including bronchogenic carcinoma (77), squamous In 6000 patients serum copper was correlated to other cell carcinoma of the larynx (1 1), cervical and other biochemistry tests obtained on the SMA 12/60. There was gynecological cancer (53), bladder ( I) and breast cancer, no definite correlation between serum copper and other (10) but not in prostate cancer. In lung cancers elevations biochemical markers such as alkaline phosphatase, lactic were found in 43 of 71 patients. A highly significant dehydrogenase, and transaminase. It was concluded that, correlation was reported between serum copper and the although serum copper elevations are not specific indicators sedimentation rate. In squamous cell carcinoma of the of particular disease, they are a relatively independent larynx, elevations were observed in I study in each of 10 parameter. In assessing serum copper in a pediatric popula patients but in another study in only 10 of 67 patients. tion, it is important to keep in mind that there is a drop in Higher copper concentrations have also been found in copper concentrations until the adult level is reached. cancerous tissue more than in normal laryngeal tissue. In In a study of 236 patients with a variety of malignant cervical cancer and in bladder cancer the elevations are lymphomas (excluding Hodgkin's disease), Hrgovcic et a!. related to the stage of the disease and decrease in response (3 1) reported a significant difference in serum copper levels to treatment. All of 23 patients with breast cancer demon related to disease activity. Levels were high in patients strated elevated serum copper levels (299 Â±34 @g/100ml) before therapy and were lowered during successful therapy compared to 20 normals (108 Â± 10 @g/lÂ®ml). In breast with an observation of concentrations within normal levels tissue the copper concentration in normal tissue ranged during remission. A recrudescence of the levels was a from less than 30 @zg/g,wet weight, to 170 and 50 to 460 premonitor of clinical relapse. The extent of elevation ;zg/g in tumor tissue. In every case the concentration in the appeared to be much greater in patients with generalized tumor tissue was greater than the homologous normal tissue disease compared to those with localized disease. There did (an average of 2.3 times greater). Copper concentrations in not appear to be any difference in the copper levels whether pleural fluid of patients with cancer did not seem to differ the disease was lymphocytic, histocytic, mixed, or undif greatly from those in benign diseases. The concentrations in ferentiated. The serum copper patterns were similar to 63 patients with breast cancer ranged from 35 to 152 zg/l00 serum copper levels reported by these authors in 191 adult ml; in 28 lung cancer patients, 62 to 121 @ig/l00 ml; in 33 patients with Hodgkin's disease (30). The elevations in lymphoma patients, 57 to 150 mg/dl; and in 62 patients with Hodgkin's disease were related to increases in ceruloplas metastatic tumors, 41 to 177 mg/dl (14). The pleural fluid mm, whereas those in liver disease were attributed to inter copper levels were related to serum copper levels and to the ference with the excretion of copper in the bile. In a study pleural fluid protein. An examination of normal adult tibia of 28 patients with Hodgkin's disease, values between 71 and osteogenic sarcoma indicated a small but significant and 131 ;Lg/ 100 ml were observed in 5 patients in corn difference in the copper levels. In the normal bone the plete remission, and values between 172 to 426 sg/ 100 ml concentration was 6.6 sg/g, dry weight, and in osteogenic were noted in 20 patients with active disease. Two other sarcoma it was 8.6 sg/g, dry weight (33). patients with active disease exhibited normal values (69 to There are a few studies concerning the cancerigenic 133 @g/lOOml in 117 normal persons). Hypercupremia effects of copper in animals. In rats the effects of DL-ethio was observed in 3 of 9 patients with reticulum cell sarcoma. nine in inducing hepatoma can be inhibited by the addition Serum copper has been evaluated as an index of tumor of 0.25% cupric acetate to the diet. The mechanism of this

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1975 American Association for Cancer Research. M. K. Schwartz inhibition is not explained. Dietary copper has also been description of selenium poisoning (52). The ratio between observed to interfere with p-dimethylaminoazobenzene liver the essential character of selenium and its toxic character is@ tumor induction (35). The cytotoxicity of 3-ethoxy-2- 1: 100. Most recently, the relationship between methionine, oxybutyraldehyde bis(thiosemicarbazone) is greatly en vitamin E, and selenium as an essential nutrient has been hanced by the presence of trace amounts of copper. As little appreciated, and glutathione peroxidase, an enzyme essen as 0.4 ppm of cupric ion activated the drug against Walker tial for peroxide protection, is selenium dependent (63). 256 tumor cells. The conclusion of the authors was that the Liver damage due to selenium ( 10 ppm as Na2SeO4) can be copper chelate of the compound was the active material prevented to some extent by addition of either DL-methio (87). It has been observed that this drug is effective as an nine, 0.50/g/ 100 ml, or DL-a-tocophenyl acetate, 0.09 antitumor agent in rats bearing tumors but is without effect g/ 100 ml, but complete protection is gained by combination in animals on a copper-deficient diet (55). treatment with methionine, 0.025 g/ 100 ml, and tocophenol, 0.05 g/ 100 ml. Other antioxidants such as N',N-diphenyl Nickel p-phenylenediamineethoxyquin (l,2-dihydroethoxy-2,2,4- A variety of nickel compounds and salts have been shown trimethylquinoline) or butylhydroxytoluene also protected to be carcinogenic. The cancerigenesis is inversely related to against the effects of selenium (40). the solubility of these compounds, and the least soluble in Near toxic levels of selenium have been reported to aqueous media appear to be the most carcinogenic. Nickel produce tumors in rats but other studies indicated that these carbonyl [Ni(CO)4J has been reported to be implicated in concentrations of selenium created chronic toxic hepatitis cancer of the lung and nasal sinuses in industrial workers that resembled hyperplasia (26, 50, 83). In the early studies, and as a possible carcinogen in tobacco smoke ( 16, 75). ingested selenium produced I I liver tumors in 53 animals The parenteral administeration of Ni(CO)4 (0.4 mg nickel who survived 18 months, but the latter investigation mdi per 100 g) at intervals of 2 or 4 weeks produced 19 tumors in cated that only hyperplastic lesions were found in the livers 121 rats. The tumors included 6 undifferentiated sarcomas, of animals that lived more than 282 days. 3 fibrosarcomas, 3 carcinomas, I hemangioendothelioma, I Dietary selenium, presumably due to its antioxidant leukemia, and 5 lymphomas. Nickel carbonyl has been properties, has been found to prevent occurrence of tumors shown to inhibit enzyme induction of cortisone-induced in animals fed or subjected to topically administered tryptophan pyrrolase and phenothiazine-induced ben carcinogens. Clayton and Bauman (7) were able to inhibit zopyrene hydroxylase, as well as protein synthesis and RNA butter yellow carcinogenesis in rats fed 5 ppm selenium, and synthesis, by means of interference with DNA-dependent Mautner et a!. (42) found that selenopurines inhibited RNA polymerase (38). lymphomas to a much greater extent that the nonconjugated Benzopyrene induction of benzopyrene hydroxylase in rat purines. lung is associated with an increase in the copper and Shamberger et a!. (69) found that previous application of manganese content of the microsomal fraction of the cell, sodium selenide, 0.0065 g/l00 ml, reduced the incidence of and a decrease in the nickel and chromium content of this carcinogenesis induced by topical application of 7,l2-di fraction (47). Phenobarbital also produces a nonspecific methylbenzanthracene and croton oil. Shamberger also re increase in microsomal copper, manganese, and zinc. It was ported a reduced incidence of 7,12-dimethylbenzanthra postulated that an early event in microsomal enzyme cene-croton oil-induced papillomas in mice by dietary induction may be a redistribution ofendogenous activity or administration of 1 ppm of selenium (67). In the mice inhibitory metals. Administration of DDT is associated with without selenium in the diet papillomas developed in 26 of enzyme induction and an increase in hepatic copper (47). 36, whereas in the animals with selenium in the diet papillomas were observed in 14 of 35 mice. The specific role ofselenium in inhibiting tumorigenesis is Beryllium not known. Selenium is known to bind loosely to proteins and is taken up rapidly by rapidly growing tumors. The In 1973 it was reported at a National Symposium on the presence of selenium in the tumor cell may successfully Current Status of Beryllium as an Occupational Hazard compete with the carcinogen for binding places of the that the rate of mortality from lung cancer in beryllium protein and thereby prevent cancerigenesis. Selenium has plant employees who previously had had beryllium-induced also been shown to interfere with genetic processess in respiratory disease was statistically significantly higher than barley and in Drosophila melanogaster (67). The protective in either all the plant employees or those who had not role of selenium in cancerigenesis is also supported by the experienced beryllium-induced respiratory distress. Deaths fact that there seem to be relationships between selenium from cancer of the liver and pnacreas in these workers also occurrence in soil and forage crops and the death rate from seemed to be related to exposure (72). cancer in the United States and Canada and between the levels of selenium in blood and the human death rate from Selenium cancer (68).

The toxicity of selenium has been known for many years. Trace Elements in Asbestos Cancerigenesis Undoubtedly, the reference in Marco Polo's diary to horses whose hooves fell off after ingesting certain plants was a Asbestos is the general term applied to a number of

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fibrous silicates. Chrysolite and crocidolite appear to be trations found in the early proliferative phase (Cyclic Days 6 more active in inducing mesotheliomas than is amosite. to 8) (24). Malignant breast tissue demonstrates much Chrysolite, crocidolite, and brucite, the magnesium hydrox higher manganese concentrations than does homologous ide outer layer of chrysolite, are carcinogenic in rats. normal tissue (49). In 9 patients the normal tissue ranged Asbestos carcinogens have been attributed to the physical from 72 to 24 @g/g,whereas the malignant tissue ranged characteristics of the fiber, contaminating trace metals, or from 10 to 55 @g/g,andin all casesthe concentration of the organic materials on the fibers. The morphological role is malignant tissue was greater than the normal. Manganese supported by findings that glass fragments of 0.06 to 3 mm was significantly higher in osteogenic sarcoma (6.6 Â±4.4 applied to pleura of rat lungs produced mesotheliomas in 12 ;Lg/g) than in normal tibia (4.6 Â± 1.6 @zg/g). Manganese is to 18% of the animals (70). involved in glycosyltransferase and other enzymes including Chromium, lead, and nickel have been found in high those needed for chondroitin sulfate synthesis and connec quantities in asbestos. In 1 sample of chrysolite, 5 mg of tive tissue metabolism (39). nickel, and 1 mg of chromium were found per g of fiber. In addition, high concentrations of zirconium, titanium, and manganese were found. Nickel is an integral portion of the Chromium fiber and additional nickel may be introduced during the milling process. It has been suggested that the fiber serves Chromium deficiency has been related to glucose metabo merely as a passive carrier of trace metals that are lism and p.o. glucose causes increases in serum chromium in responsible for the carcinogenesis. It has also been reported normal persons but not in diabetics. The normal serum that trace metals interfere with the metabolism of ben concentration is about 2.5 @g/ml. A precise role for zopyrene in the lung and maintain its presence in the cell for chromium in cancerigenesis has not been defined. It may longer periods of time (8, 15, 27, 64). The inhibition of play a role in association with calcium in the stabilization of benzopyrene hydroxylase (aryl polycyclic hydroxylase) by nuclear nucleic acids (3). nickel has been proposed as a mechanism for nickel cancerigenesis (73). Other Elements Microsomal copper and manganese were increased and microsomal nickel and chromium were decreased 72 hr There is little information available concerning the func after the intratracheal administration of benzopyrene, tion of other essential elements in cancer. Cobalt concentra which produced a 6-fold increase in lung aryl hydrocarbon tions in osteogenic sarcoma are not significantly different hydroxylase activity. Lung microsomal copper increased from those in normal bone. The level of cobalt in DNA 4-fold over control levels with no changes in the other extracted from Walker 256 and sarcoma M.l cells is much subcellular copper levels. There was 40% increase in micro higher than that from normal rat liver. Tin levels have been somal manganese, but a 40% decrease in nuclear man reported to be lower in some cancer tissues than in ganese. The microsomal concentrations of nickel and homologous normal tissues. The significance of these find chromium were reduced to almost nondetectable levels. The ings is unknown. trace metals may play a role in the regulation of microsomal enzyme activity in rat lung by altering the affinity of the References substrates for cytochrome P-450 or by altering the specific ity of the substrate heme protein affinity for the active site I. Albert, L., Hienzsch, E., Arndt, J., and Kriester, A. Bedewtung und of the enzyme (47). Vevanderungen des Serum-Kupferspiegels Wahrend und nach der @ Bestrahlung von Harnblasenkarzinomen. Z. Urol., 8: 561 566, 1972. Manganese 2. Andronikashvili, E. L., Mosulishvili, L. M.. Belokobilski, A. I., Kharabadze, N. E., Terzieva, T. K., and Efremova, E. Y. Content of Some Trace Elements in Sarcoma M-l DNA in Dynamics of Manganese is increased in serum of patients during the Malignant Growth. Cancer Res., 34: 27 1-274, 1974. active phase of acute icteric viral hepatitis. The mean value 3. Anghileri, L. J. Calcium Metabolism in Tumorsâ€”Its Relationship in the patients is 2.32 Â±0.96 ng/ml compared to 0.57 Â±13 with Chromium Complex Accumulation. Oncology, 27: 30 44. 1973. ng/ml in normals. The levels return toward normal in the 4. Briggs, M. H., Garcia-Weis, P., Wallace, E., and Briggs, M. Zinc subsiding phase of the disease. In postnecrotic cirrhosis, the Deficiency in Man. Lancet, 2: 1396, 1973. serum but not the packed RBC manganese levels were also 5. Burr, R. G. Plasma-Zinc Levels. Lancet, I: 879, 1974. significantly elevated. There is a significant correlation of 6. Chvapil, M. New Aspects in the Biological Role of Zinc: A Stabilizer serum manganese and both bilirubin and aspartate amino of Macromolecules and Biological Membranes. Life Sci.. 13: transferase in these patients. The increases were presumably 1041-1049,1973. 7. Clayton, C. C., and Bauman, C. A. Diet and Azo Dye Tumors: Effect due to either release of hepatic manganese during parenchy of Diet during a Period When the Dye Is Not Fed. Cancer Res., 9: mal necrosis or decreased hepatobiliary excretion (88). The 575-582,1949. liver has a relatively high concentration of manganese (1.5 8. Cralley, L. J. Electromotive Phenomenon in Metal and Mineral Â± 2 @g/g,wet weight) and manganese isprimarily excreted Particulate Exposures; Relevance to Exposure to Asbestos and Occur into the bile. Manganese concentrations in normal human rence ofCancer. J. Am. Med. Hyg. Assoc.. 32: 653, 1971. endometrium and in plasma are cyclic with highest concen 9. Davies, I. J., Musa, M., and Dormandy, T. L. Measurementsof

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PlasmaZinc. I. In Health and Disease.J. Clin. Pathol., 21: 359-365, 30. Hrgovcic, M., Tessmer, C. F., Thomas, F. B., Fuller, L. M., Gamble, 1968. J. F.,andShullenberger,C.C. SignificanceofSerumCopperLevelsin 10. DeJorge, F. B., Goes, J. S., Jr., Guedes, J. L., and DeUlhoa Cintra, A. Adult Patients with Hodgkin's Disease. Cancer, 31: 1337-1345, 1973. B. Biochemical Studies on Copper, Copper Oxidase, Magnesium, 31. Hrgovcic, M., Tessmer,C. F., Thomas, F. B., Ong, P. 5., Gamble,J. Sulfur, Calcium and Phosphorus in Cancer of the Breast. Clin. Chim. F., andShullenberger,C.C. SerumCopperObservationsinPatients Acta, 12: 403-406, 1965. with Malignant Lymphoma. Cancer, 32: 15I 2- 1524, 1973. lI. Deiorge, F. B., Paiva, L., Mion, P., and DaNova, R. Biochemical 32. Ilicin, G. Serum Copper and Magnesium Levels in Leukemia and Studies on Serum Copper, Copper Oxidase, Magnesium, Sulfur, Malignant Lymphoma. Lancet, 2: 1036-1037,1971. Calcium and Phosphorus in Cancer of the Larynx. Acta Oto-Laryn 33. 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Cancer Res 1975;35:3481-3487.

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