[CANCER RESEARCH35,3481-3487,Novcmbcr1975]

jurious effects of hydrogen peroxide; and vanadium blockscholesterol biosynthesis.

In animal deficiency studies it has been determined thatselenium can prevent muscular dystrophy and liver necrosisin rats and white muscle disease in cattle. Chromium isneeded for growth of rats and its deficiency leads to areduced life-span, corneal lesions, and interference withinsulin action producing a diabetic state with removal ofglucose from the blood at a rate that is one-half that ofanimals on a chromium-containing diet. In other animaldeprivation studies the growth of rats was only two-thirdsthat of control animals if the diet contained less than I to 2ppm of tin or less than 0. 1 ppm of vanadium. Fluoride isessential for growth of rats, silicon is needed for thedevelopment of skeleton and feathers of young chicks, andnickel is essential for the growth of wing and tail feathers(20).

The effects of trace elements are related to concentrationand recorded observations range from a deficiency state, tofunction as biologically essential components, to an unbalance when excess of one element interferes with the functionof another, to pharmacologically active concentrations (i.e.,zinc in healing), and finally to toxic and even life-threatening concentrations (85). The purpose of this review is toconsider the trace elements from the standpoint of boththeir role in carcinogenesis and the possible use of theirassay in biological fluids as diagnostic or prognostic aidsin patients with cancer. Iron and iodide will not beconsidered since they have been the subject of many reviewsand, although present in relatively small concentrations,they are psychologically, if not physiologically, not “traceelements. “The review will not consider such elements asarsenic or mercury that have been shown to be cancerigenic,but are not essential for animal growth (21, 51, 89).

Zinc

Reports of zinc values in biological fluids of cancerpatients have been variable. Serum yields higher zinc levelsthan does plasma, presumably due to platelet breakdown.There is a diurnal variation in serum zinc concentrations,and zinc values less than the fasting concentrations areobserved for 2 to 3 hr after the ingestion of food. In additionthere is a decline in zinc levels with increasing age andwomen demonstrate lower levels than men (5). NormalRBC contain about 10 times the concentration of zinc seenin serum,and about 30%ofserum zinc is bound to albumin.Zinc is presumably transported bound to a specific a2-glycoprotein (22). Because of the possible variables in serum

Summary

The review considers trace elements including fluorine,copper, manganese, zinc, cobalt, chromium, selenium,molybdenum, tin, vanadium, silicon, and nickel from thestandpoint of their role as either inhibitory or causativeagents of cancer and also the possible use of their assay inbiological fluids as diagnostic or prognostic aids in patientswith cancer.

Introduction

The role of trace metals in cancer has been the subject ofconjecture, and reports of different authors are oftenconflicting and contradictory. A major reason for thesediscrepancies is the difficulty in analyzing trace elementsand the problems that exist in collecting specimens withoutcontamination (82). Trace elements are required in smallconcentrations as essential components of biological enzyme systems or of structural portions of biologically activeconstituents. They constitute, in toto, less than 0.01 % byweight of the total body composition and those thus fardefined as essential in animal deficiency experiments includeiron, iodine, fluorine, copper, manganese, zinc, cobalt,chromium, selenium, molybdenum, tin, vanadium, andpossibly silicon and nickel (20). The metals (all of the aboveexcept idodine, fluorine, and selenium) play their mostimportant role as cofactors in enzymes. Iron is an importantconstituent of succinate dehydrogenase as well as a part ofthe heme of hemoglobin, myoglobin, and the cytochromes.Zinc is involved in carbonic acid (carbonic anhydrase), andin alcohol (alcohol dehydrogenase) formation, and in proteolysis (carboxypeptidase, leucine aminopeptidase, etc.)(4). Copper is present in many enzymes involved in oxidation (tyrosinase, ceruloplasmin, amine oxidase, cytochromeoxidase), and manganeseis a part of enzymesinvolved inurea formation, pyruvate metabolism, and the galactotransferase of connective tissue biosynthesis. In addition toits role in vitamin 12,cobalt is also a cofactor of enzymesinvolved in DNA biosynthesis and amino acid metabolism.Molybdenum plays an important role in purine metabolism; selenium is related to glutathione peroxidase, an enzyme involved in the protection of hemoglobin against in

1 Presented at the conference on Nutrition in the Causation of Cancer,

May 19 to 22, 1975, Key Biscayne, Fla. This review was supported in partby USPHS Grant CA 08748from the National Cancer Institute.

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Role of Trace Elements in Cancer'

Morton K. Schwartz

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

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M. K. Schwartz

zinc levels, it has been suggested that RBC zinc concentrations may be a better indicator of zinc deficiency states.

Low serum zinc levels have been observed in serum ofpatients with cancer of the bronchus and colon, but not inother forms of cancer (9), and in RBC, leukocytes, andgranulocytes of such patients (37, 76, 86). “Hypozincemia―is a nonspecific observation and decreased serum zinc levelshave been found in cirrhosis, hepatitis (88), lung infectionsincluding tuberculosis, myocardial infarction, renal insufficiency, diseases producing increased muscle metabolism,acute tissue injury (41, 82), and pregnant women (61).Steroid therapy, including administration of p.o. contraceptives, also produces a hypozincemia (18, 19).

Patients with cancer excrete as much as 3 times more zincin their urine than do normal persons and in such patientsthe molybdenum excretion is decreased. Pfeilsticher (56)suggested that a ratio of urinary zinc to molybdenum of> 300 is indicative of advanced cancer. Zinc levels are lowerin prostatic cancer tissue than in normal prostate tissue, butthey are increased in benign prostatic hypertrophy tissue(23). Liver, kidney, or lung harboring metastasis has ahigher zinc content than does the corresponding normaltissue or the tumor itself (34, 90). The liver of patients withacute viral hepatitis contains less zinc than does normal liverand is accompanied by increased zinc in the urine butnormal levels in serum.

Kew and Mallett (36) reported that in normal liver tissuethe zinc concentration is about 78 ±41 @g/g,wet weight;that of noncirrhotic liver tissue from patients with primaryliver cancer is about 75 ±31 @ig/g;cirrhotic liver tissue fromthese patients is about 45 ±23 zg/g, and the primary livercancer itself is about I 8 ±7 @.tg/g.Low zinc levels have beenreported in hepatic metastases from a variety of sourceswith greater than normal values in the liver harboring thecancer. Olson et a!. (54) reported increased liver zincconcentrations in patients with cancer, and McBean et a!.(43) found increased liver and kidney zinc in patients withbronchogenic, gastric, and nasopharyngeal cancer. Liverzinc concentrations of patients dying from noncancerousdisease have been reported to be similar to that of individuals dying in accidents (43).

It has been reported that cancerous lung and breast tissuehave a higher zinc concentration than does normal tissue(49). In I study the mean zinc concentration ofbreast cancertissue was 5.7 times that of normal breast tissue. The valuesin various patients were extremely variable (66). Forexample in one patient the tumor had 490zg/g oftissue andnormal tissue 240 @g/g,whereas in a specimen from another patient the zinc concentration was 2.2 jsg/g in thenormal tissue and 1.8 @sg/gin the tumor. An increased uptake of 5Zn has been found in mammary tumors of mice(84). In bones from normal individuals (human tibia) andin osteogenic sarcoma tissue, a significant difference inzinc concentration was observed (33). In 40 control specimens the value was 147. 1 ±49.8 .tg/g, dry weight, compared to 465.8 ± 578.6 jzg/g in 8 osteogenic sarcomaspecimens.

The role of zinc as a carcinogenic agent is still subject tocontroversy. Excessive intake p.o. has been reported to be

related to cancer of the esophagus and stomach (44, 71).Poswillo and Cohen (60) found that ingestion of zincinhibited the development of tumors. It has been reportedthat a dietary deficiency of zinc inhibits the growth ofWalker 256 carcinosarcoma (I 3, 45) and Lewis lungcarcinoma (12). Survival of mice with transplanted leukemia or an ascites carcinoma was also prolonged by thedeficiency (I 2). These effects were attributed to a zincdeficiency interfering wuth DNA synthesis (65). Guthrieand Guthrie (22) found that injection of 0.05 ml of 4% zincchloride into the testes of Syrian hamsters produced embryonal carcinomas (testicular teratoma) in 2 of 49 animals.Zinc metal powder injected into the trachea and pleura ofrats produced reticulosarcomas in the lungs and seminomasin the testicles in 15% of the animals (17).

An important consideration for the cancer patient is theobservation that there is delayed healing in patients withzinc deficiency (28) and zinc, when administered p.o. topostoperative patients, greatly accelerates healing (25,57—59).Zinc sulfate p.o. increased the healing rate of bedsores and leg ulcers when the serum zinc concentrationbefore treatment was 110 zg/ 100 ml but not in patients withgreater serum levels (61). This has been attributed to therole of zinc in protein synthesis and collagen formation.Zinc, by virtue of its presence in RNA and DNA polymerase, may account for reports of its role in regeneration of ratliver (62).

The exact role of zinc is unknown. Zinc binding may berelated to cancerigenesis in the sense that the metals mayeffect catabolic or anabolic enzymes. Chvapil (6) hasproposed that zinc is an integral part ofbiomembranes, maycontrol membrane integrity, and may be involved in thestability of membranes and in lipid peroxidation-relatedinjury. Zinc has been observed to function as a mitogeninducing blastogen transformation of lymphocytes in afashion similar to that of phytohemagglutinin. Phytohemagglutinin effects are also greater in lymphocytes harvestedfrom rats that had been given a high zinc diet. The role ofzinc in RNA and DNA polymerase, its inhibitory effects onphosphodiesterase, and its activating effect on membranebound adenyl cyclase, suggest a role for zinc in cancerigenesis. Zinc also has been shown to stabilize ribosomes and theDNA double helix. The zinc content of DNA and RNA,isolated from Walker 256 carcinosarcoma and sarcoma M.I, was greater than that in these nucleic acids isolated fromlivers of normal rats. Andronikashvili et a!. (2) found that inDNA and RNA purified from sarcomas the zinc concentration remained constant following transplantation, but theiron, antimony, chromium, cobalt, and selenium decreased.It was concluded that the zinc was a necessary part of thegrowth process but that the other elements were not.

Copper

Copper is primarily found in serum (95%) as part of theoxidative enzyme ceruloplasmin, an a2-glycoprotein with amolecular weight of about 150,000. The remainder ispresent in an ionic form loosely bound to albumin. The dailyadult requirement is about 2 mg/day and the majority of the

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response to radiotherapy (79). In Hodgkin's disease serumcopper determinations are useful indicators of the effectiveness of chemotherapeutic regimens used in obtainingthe 1st treatment response and then as an early indicatorof reactivation of disease. Elevations may occur 1 to 6months before clinical evidence of relapse has occurred(28). Similar serum copper levels have been observed inchildren with Hodgkin's disease (81).

In patients with leukemia, normal values were observed in12 pediatric patients with acute lymphocytic leukemia whowere in complete remission. In 8 patients with activedisease, increased percentages of bone marrow blast cellswere associated with abnormal serum copper concentrations(78, 80). Similar observations were made in 265 pediatricand 89 adult patients with acute lymphatic leukemia (29).The development of tumors in mice after administration ofMaloney murine rhabdomyosarcoma virus is preceded byan increase in serum copper as is the induction of reticulumcell sarcoma-like lesions in marmosets by Herpes saimiri, orthe growth of Morris hepatoma after s.c. implantation inrats (46).

Serum copper has also been found elevated in other formsof cancer including bronchogenic carcinoma (77), squamouscell carcinoma of the larynx (1 1), cervical and othergynecological cancer (53), bladder ( I ) and breast cancer,(10) but not in prostate cancer. In lung cancers elevationswere found in 43 of 71 patients. A highly significantcorrelation was reported between serum copper and thesedimentation rate. In squamous cell carcinoma of thelarynx, elevations were observed in I study in each of 10patients but in another study in only 10 of 67 patients.Higher copper concentrations have also been found incancerous tissue more than in normal laryngeal tissue. Incervical cancer and in bladder cancer the elevations arerelated to the stage of the disease and decrease in responseto treatment. All of 23 patients with breast cancer demonstrated elevated serum copper levels (299 ±34 @g/100 ml)compared to 20 normals (108 ± 10 @g/l®ml). In breasttissue the copper concentration in normal tissue rangedfrom less than 30 @zg/g,wet weight, to 170 and 50 to 460;zg/g in tumor tissue. In every case the concentration in thetumor tissue was greater than the homologous normal tissue(an average of 2.3 times greater). Copper concentrations inpleural fluid of patients with cancer did not seem to differgreatly from those in benign diseases. The concentrations in63 patients with breast cancer ranged from 35 to 152 zg/l00ml; in 28 lung cancer patients, 62 to 121 @ig/l00 ml; in 33lymphoma patients, 57 to 150 mg/dl; and in 62 patients withmetastatic tumors, 41 to 177 mg/dl (14). The pleural fluidcopper levels were related to serum copper levels and to thepleural fluid protein. An examination of normal adult tibiaand osteogenic sarcoma indicated a small but significantdifference in the copper levels. In the normal bone theconcentration was 6.6 sg/g, dry weight, and in osteogenicsarcoma it was 8.6 sg/g, dry weight (33).

There are a few studies concerning the cancerigeniceffects of copper in animals. In rats the effects of DL-ethionine in inducing hepatoma can be inhibited by the additionof 0.25% cupric acetate to the diet. The mechanism of this

ingested copper is rapidly converted in the liver to ceruloplasmin. Cellular copper is primarily found in mitochondna, and the adult body contains about 100 to 150 mg withthe highest organ concentration in liver, kidney, heart,brain, and pancreas. Only 10 to 60 zg of copper are excretedin the urine each day.

The role of copper, hypocupremia, and elevated livercopper concentrations in Wilson's disease are well documented and the effects of copper toxicity have been clearlydescribed. Deficiency states have been reported in malabsorption (kwashiorkor, sprue, celiac disease), marasmicinfants, infants with Mentes kinky hair syndrome, andnephrotic syndrome. Elevations of serum copper have beenreported in multiple sclerosis, infection, myocardial infarction, acute and chronic liver disease, and schizophrenia (74).There is a relationship between serum copper and inflammation, and in some patients, but not all, there is a directcorrelation with C-reactive protein. In patients with lymphomatous diseases the role of copper has been the subjectof considerable investigation (32, 48). Elevated serumcopper has also been reported following administration ofestrogens or thyroid and pituitary hormones and aftersurgery (31).

In 6000 patients serum copper was correlated to otherbiochemistry tests obtained on the SMA 12/60. There wasno definite correlation between serum copper and otherbiochemical markers such as alkaline phosphatase, lacticdehydrogenase, and transaminase. It was concluded that,although serum copper elevations are not specific indicatorsof particular disease, they are a relatively independentparameter. In assessing serum copper in a pediatric population, it is important to keep in mind that there is a drop incopper concentrations until the adult level is reached.

In a study of 236 patients with a variety of malignantlymphomas (excluding Hodgkin's disease), Hrgovcic et a!.(3 1) reported a significant difference in serum copper levelsrelated to disease activity. Levels were high in patientsbefore therapy and were lowered during successful therapywith an observation of concentrations within normal levelsduring remission. A recrudescence of the levels was apremonitor of clinical relapse. The extent of elevationappeared to be much greater in patients with generalizeddisease compared to those with localized disease. There didnot appear to be any difference in the copper levels whetherthe disease was lymphocytic, histocytic, mixed, or undifferentiated. The serum copper patterns were similar toserum copper levels reported by these authors in 191 adultpatients with Hodgkin's disease (30). The elevations inHodgkin's disease were related to increases in ceruloplasmm, whereas those in liver disease were attributed to interference with the excretion of copper in the bile. In a studyof 28 patients with Hodgkin's disease, values between 71and 131 ;Lg/ 100 ml were observed in 5 patients in cornplete remission, and values between 172 to 426 sg/ 100 mlwere noted in 20 patients with active disease. Two otherpatients with active disease exhibited normal values (69 to133 @g/lOOml in 117 normal persons). Hypercupremiawas observed in 3 of 9 patients with reticulum cell sarcoma.Serum copper has been evaluated as an index of tumor

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description of selenium poisoning (52). The ratio betweenthe essential character of selenium and its toxic character is@1: 100. Most recently, the relationship between methionine,vitamin E, and selenium as an essential nutrient has beenappreciated, and glutathione peroxidase, an enzyme essential for peroxide protection, is selenium dependent (63).Liver damage due to selenium ( 10 ppm as Na2SeO4) can beprevented to some extent by addition of either DL-methionine, 0.50/g/ 100 ml, or DL-a-tocophenyl acetate, 0.09g/ 100 ml, but complete protection is gained by combinationtreatment with methionine, 0.025 g/ 100 ml, and tocophenol,0.05 g/ 100 ml. Other antioxidants such as N',N-diphenylp-phenylenediamineethoxyquin (l,2-dihydroethoxy-2,2,4-trimethylquinoline) or butylhydroxytoluene also protectedagainst the effects of selenium (40).

Near toxic levels of selenium have been reported toproduce tumors in rats but other studies indicated that theseconcentrations of selenium created chronic toxic hepatitisthat resembled hyperplasia (26, 50, 83). In the early studies,ingested selenium produced I I liver tumors in 53 animalswho survived 18 months, but the latter investigation mdicated that only hyperplastic lesions were found in the liversof animals that lived more than 282 days.

Dietary selenium, presumably due to its antioxidantproperties, has been found to prevent occurrence of tumorsin animals fed or subjected to topically administeredcarcinogens. Clayton and Bauman (7) were able to inhibitbutter yellow carcinogenesis in rats fed 5 ppm selenium, andMautner et a!. (42) found that selenopurines inhibitedlymphomas to a much greater extent that the nonconjugatedpurines.

Shamberger et a!. (69) found that previous application ofsodium selenide, 0.0065 g/l00 ml, reduced the incidence ofcarcinogenesis induced by topical application of 7,l2-dimethylbenzanthracene and croton oil. Shamberger also reported a reduced incidence of 7,12-dimethylbenzanthracene-croton oil-induced papillomas in mice by dietaryadministration of 1 ppm of selenium (67). In the micewithout selenium in the diet papillomas developed in 26 of36, whereas in the animals with selenium in the dietpapillomas were observed in 14 of 35 mice.

The specific role ofselenium in inhibiting tumorigenesis isnot known. Selenium is known to bind loosely to proteinsand is taken up rapidly by rapidly growing tumors. Thepresence of selenium in the tumor cell may successfullycompete with the carcinogen for binding places of theprotein and thereby prevent cancerigenesis. Selenium hasalso been shown to interfere with genetic processess inbarley and in Drosophila melanogaster (67). The protectiverole of selenium in cancerigenesis is also supported by thefact that there seem to be relationships between seleniumoccurrence in soil and forage crops and the death rate fromcancer in the United States and Canada and between thelevels of selenium in blood and the human death rate fromcancer (68).

Trace Elements in Asbestos Cancerigenesis

Asbestos is the general term applied to a number of

inhibition is not explained. Dietary copper has also beenobserved to interfere with p-dimethylaminoazobenzene livertumor induction (35). The cytotoxicity of 3-ethoxy-2-oxybutyraldehyde bis(thiosemicarbazone) is greatly enhanced by the presence of trace amounts of copper. As littleas 0.4 ppm of cupric ion activated the drug against Walker256 tumor cells. The conclusion of the authors was that thecopper chelate of the compound was the active material(87). It has been observed that this drug is effective as anantitumor agent in rats bearing tumors but is without effectin animals on a copper-deficient diet (55).

Nickel

A variety of nickel compounds and salts have been shownto be carcinogenic. The cancerigenesis is inversely related tothe solubility of these compounds, and the least soluble inaqueous media appear to be the most carcinogenic. Nickelcarbonyl [Ni(CO)4J has been reported to be implicated incancer of the lung and nasal sinuses in industrial workersand as a possible carcinogen in tobacco smoke ( 16, 75).

The parenteral administeration of Ni(CO)4 (0.4 mg nickelper 100 g) at intervals of 2 or 4 weeks produced 19 tumors in121 rats. The tumors included 6 undifferentiated sarcomas,3 fibrosarcomas, 3 carcinomas, I hemangioendothelioma, Ileukemia, and 5 lymphomas. Nickel carbonyl has beenshown to inhibit enzyme induction of cortisone-inducedtryptophan pyrrolase and phenothiazine-induced benzopyrene hydroxylase, as well as protein synthesis and RNAsynthesis, by means of interference with DNA-dependentRNA polymerase (38).

Benzopyrene induction of benzopyrene hydroxylase in ratlung is associated with an increase in the copper andmanganese content of the microsomal fraction of the cell,and a decrease in the nickel and chromium content of thisfraction (47). Phenobarbital also produces a nonspecificincrease in microsomal copper, manganese, and zinc. It waspostulated that an early event in microsomal enzymeinduction may be a redistribution ofendogenous activity orinhibitory metals. Administration of DDT is associated withenzyme induction and an increase in hepatic copper (47).

Beryllium

In 1973 it was reported at a National Symposium on theCurrent Status of Beryllium as an Occupational Hazardthat the rate of mortality from lung cancer in berylliumplant employees who previously had had beryllium-inducedrespiratory disease was statistically significantly higher thanin either all the plant employees or those who had notexperienced beryllium-induced respiratory distress. Deathsfrom cancer of the liver and pnacreas in these workers alsoseemed to be related to exposure (72).

Selenium

The toxicity of selenium has been known for many years.Undoubtedly, the reference in Marco Polo's diary to horseswhose hooves fell off after ingesting certain plants was a

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fibrous silicates. Chrysolite and crocidolite appear to bemore active in inducing mesotheliomas than is amosite.Chrysolite, crocidolite, and brucite, the magnesium hydroxide outer layer of chrysolite, are carcinogenic in rats.Asbestos carcinogens have been attributed to the physicalcharacteristics of the fiber, contaminating trace metals, ororganic materials on the fibers. The morphological role issupported by findings that glass fragments of 0.06 to 3 mmapplied to pleura of rat lungs produced mesotheliomas in 12to 18% of the animals (70).

Chromium, lead, and nickel have been found in highquantities in asbestos. In 1 sample of chrysolite, 5 mg ofnickel, and 1 mg of chromium were found per g of fiber. Inaddition, high concentrations of zirconium, titanium, andmanganese were found. Nickel is an integral portion of thefiber and additional nickel may be introduced during themilling process. It has been suggested that the fiber servesmerely as a passive carrier of trace metals that areresponsible for the carcinogenesis. It has also been reportedthat trace metals interfere with the metabolism of benzopyrene in the lung and maintain its presence in the cell forlonger periods of time (8, 15, 27, 64). The inhibition ofbenzopyrene hydroxylase (aryl polycyclic hydroxylase) bynickel has been proposed as a mechanism for nickelcancerigenesis (73).

Microsomal copper and manganese were increased andmicrosomal nickel and chromium were decreased 72 hrafter the intratracheal administration of benzopyrene,which produced a 6-fold increase in lung aryl hydrocarbonhydroxylase activity. Lung microsomal copper increased4-fold over control levels with no changes in the othersubcellular copper levels. There was 40% increase in microsomal manganese, but a 40% decrease in nuclear manganese. The microsomal concentrations of nickel andchromium were reduced to almost nondetectable levels. Thetrace metals may play a role in the regulation of microsomalenzyme activity in rat lung by altering the affinity of thesubstrates for cytochrome P-450 or by altering the specificity of the substrate heme protein affinity for the active siteof the enzyme (47).

Manganese

Manganese is increased in serum of patients during theactive phase of acute icteric viral hepatitis. The mean valuein the patients is 2.32 ±0.96 ng/ml compared to 0.57 ±13ng/ml in normals. The levels return toward normal in thesubsiding phase of the disease. In postnecrotic cirrhosis, theserum but not the packed RBC manganese levels were alsosignificantly elevated. There is a significant correlation ofserum manganese and both bilirubin and aspartate aminotransferase in these patients. The increases were presumablydue to either release of hepatic manganese during parenchymal necrosis or decreased hepatobiliary excretion (88). Theliver has a relatively high concentration of manganese (1.5± 2 @g/g,wet weight) and manganese isprimarily excreted

into the bile. Manganese concentrations in normal humanendometrium and in plasma are cyclic with highest concen

trations found in the early proliferative phase (Cyclic Days 6to 8) (24). Malignant breast tissue demonstrates muchhigher manganese concentrations than does homologousnormal tissue (49). In 9 patients the normal tissue rangedfrom 72 to 24 @g/g,whereas the malignant tissue rangedfrom 10 to 55 @g/g,and in all cases the concentration of themalignant tissue was greater than the normal. Manganesewas significantly higher in osteogenic sarcoma (6.6 ±4.4;Lg/g) than in normal tibia (4.6 ± 1.6 @zg/g). Manganese is

involved in glycosyltransferase and other enzymes includingthose needed for chondroitin sulfate synthesis and connective tissue metabolism (39).

Chromium

Chromium deficiency has been related to glucose metabolism and p.o. glucose causes increases in serum chromium innormal persons but not in diabetics. The normal serumconcentration is about 2.5 @g/ml. A precise role forchromium in cancerigenesis has not been defined. It mayplay a role in association with calcium in the stabilization ofnuclear nucleic acids (3).

Other Elements

There is little information available concerning the function of other essential elements in cancer. Cobalt concentrations in osteogenic sarcoma are not significantly differentfrom those in normal bone. The level of cobalt in DNAextracted from Walker 256 and sarcoma M.l cells is muchhigher than that from normal rat liver. Tin levels have beenreported to be lower in some cancer tissues than inhomologous normal tissues. The significance of these findings is unknown.

References

I. Albert, L., Hienzsch, E., Arndt, J., and Kriester, A. Bedewtung undVevanderungen des Serum-Kupferspiegels Wahrend und nach derBestrahlung von Harnblasenkarzinomen. Z. Urol., 8: 561@ 566, 1972.

2. Andronikashvili, E. L., Mosulishvili, L. M.. Belokobilski, A. I.,Kharabadze, N. E., Terzieva, T. K., and Efremova, E. Y. Content ofSome Trace Elements in Sarcoma M-l DNA in Dynamics ofMalignant Growth. Cancer Res., 34: 27 1-274, 1974.

3. Anghileri, L. J. Calcium Metabolism in Tumors—Its Relationshipwith Chromium Complex Accumulation. Oncology, 27: 30 44. 1973.

4. Briggs, M. H., Garcia-Weis, P., Wallace, E., and Briggs, M. ZincDeficiency in Man. Lancet, 2: 1396, 1973.

5. Burr, R. G. Plasma-Zinc Levels. Lancet, I: 879, 1974.6. Chvapil, M. New Aspects in the Biological Role of Zinc: A Stabilizer

of Macromolecules and Biological Membranes. Life Sci.. 13:1041-1049,1973.

7. Clayton, C. C., and Bauman, C. A. Diet and Azo Dye Tumors: Effectof Diet during a Period When the Dye Is Not Fed. Cancer Res., 9:575-582,1949.

8. Cralley, L. J. Electromotive Phenomenon in Metal and MineralParticulate Exposures; Relevance to Exposure to Asbestos and Occurrence ofCancer. J. Am. Med. Hyg. Assoc.. 32: 653, 1971.

9. Davies, I. J., Musa, M., and Dormandy, T. L. Measurementsof

NOVEMBER 1975 3485

on May 24, 2020. © 1975 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

M. K. Schwartz

PlasmaZinc. I. In Health and Disease.J. Clin. Pathol., 21: 359-365,1968.

10. DeJorge, F. B., Goes, J. S., Jr., Guedes, J. L., and DeUlhoa Cintra, A.B. Biochemical Studies on Copper, Copper Oxidase, Magnesium,Sulfur, Calcium and Phosphorus in Cancer of the Breast. Clin. Chim.Acta, 12: 403-406, 1965.

lI. Deiorge, F. B., Paiva, L., Mion, P., and DaNova, R. BiochemicalStudies on Serum Copper, Copper Oxidase, Magnesium, Sulfur,Calcium and Phosphorus in Cancer of the Larynx. Acta Oto-Laryngol.,62.454-458,1966.

12. DeWys, W. D., and Poires, W. Inhibition of a Spectrum of AnimalTumors by Dietary Zinc Deficiency. J. NatI. Cancer Inst., 48:375-381,1972.

13. DeWys, W. D., Poires, W. J., Richter, M. C., and Strain, W. H.Inhibition of Walker 256 Carcinosarcoma Growth by Dietary ZincDeficiency. Proc. Soc. Exptl. Biol. Med., 135: 17-22, 1970.

14. Dines, D. E., Elveback, L. R., and McCall, J. T. Zinc, Copper, andIron Content of Pleural Fluid in BenignandNeoplasticDisease.MayoClin. Proc., 49: 102-106, 1974.

15. Dixon, J. R., Lowe, D. B., Richards, D. E., Cralley, L. J., andStockinger, H. E. The Role oflrace Metals in Chemical Carcinogenesis Asbestos Cancers. Cancer Res., 30: 1068—1075, 1970.

16. Doll, R., Morgan, L. G., and Spiezen, F. E. Cancers of the Lung andNasal Sinuses in Nickel Workers. Brit. J. Cancer, 24: 623-632, 1970.

17. Dvizhkov, P. P., and Potapova, I. M. Blastomogenic Properties ofMetal Zinc and Zinc Chloride. (Transl. from Russian.) Intern. J.Vitalstoffe Zivilisationskrankh., 2: 23-29, 1970.

18. Flynn, A., Poires, W. J., Strain, W. W., Hill, 0. A., Jr., and Fratianne,R. B. Rapid SerumZinc DepletionAssociatedwith CorticosteroidTherapy. Lancet, 2: 1169-1172,1971.

19. Flynn, A., Strain, W. H., Poires, W. J., and Hill, 0. A., Jr. ZincDeficiency with Altered Adrenocortical Function and Its Relation toDelayed Healing. Lancet, 1: 789-791, 1973.

20. Frieden, E. The Chemical Elements of Life. Sci. Am., 227: 52—60,1972.

21. Furst, A. Chelation and Cancer—A Speculative Review. in: M. J.Seven, and L. A. Johnson (eds.), Metal-Binding in Medicine, pp.336-343. Philadelphia: J. P. Lippincott Co., 1960.

22. Guthrie, J., and Guthrie, 0. A. Embryonal Carcinoma in SyrianHamsters after Intratesticular Inoculation of Zinc Chloride DuringSeasonal Testicular Growth. Cancer Res., 34: 2612-2614, 1974.

23. Gyorkey, F., Miri, K., Huff, J. A., and Gyorkey, P. Zinc andMagnesium in Human Prostate Gland. Normal Hyperplastic andNeoplastic. Cancer Res., 27: 1348-1353, 1967.

24. Hagenfeldt, K., Plantin, L. D., and Diczfalusy, E. Trace Elements inthe Human Endometrium. Acta Endocrinol., 72: 115-126, 1973.

25. Hallbook, T., and Lanner, E. Serum Zinc and Healing in Venous LegUlcers. Lancet, 2: 780-782, 1972.

26. Harr, J. R., Bone, J. F., Tinsley, J. J., Weisig, P. H., and Yamamoto,R. S. Selenium Toxicity in Rats. II. Histopathology. in. 1966Symposium, Selenium in Biomedicine, pp. 163-178. Westport, Conn.:AVI PublishingCo., 1967.

27. Harrington, J. S. Chemical Factors Including Trace Elements. in: P.Bogovski, V. Timbrels, J. L. Gilson, and J. C. . Wagner (eds.),Etiological Mechanisms in Biological Effects of Asbestos, pp.304-31 1. Lyon, France: International Agency for Research on Cancer,1973.

28. Hrgovic, M.. Tessmer, C. F., Minckler, T. M., Mosler, B., and Taylor,G. H. SerumCopperLevelsin Lymphomaand Leukemia:SpecialReference to Hodgkin's Disease. Cancer, 2!: 743-155, 1968.

29. Hrgovcic, M., Tessmer, C. F., Brown, B. W., Wilbur, J. K., Mumford,D. M.. Thomas.F. B., Shullenberger,C. C., andTaylor,G. SerumCopper Studies in the Lymphomas and Acute Leukemia. In: I. M.Arid (ed), Progress in Clinical Cancer, Vol. 5, pp. 121-153. NewYork: Grune and Stratton, 1973.

30. Hrgovcic, M., Tessmer, C. F., Thomas, F. B., Fuller, L. M., Gamble,J. F.,andShullenberger,C.C. SignificanceofSerumCopperLevelsinAdult Patients with Hodgkin's Disease. Cancer, 31: 1337-1345, 1973.

31. Hrgovcic, M., Tessmer,C. F., Thomas, F. B., Ong, P. 5., Gamble,J.F., andShullenberger,C. C. SerumCopperObservationsin Patientswith Malignant Lymphoma. Cancer, 32: 15I 2- 1524, 1973.

32. Ilicin, G. Serum Copper and Magnesium Levels in Leukemia andMalignant Lymphoma. Lancet, 2: 1036-1037,1971.

33. Janes, J. M., McCall, J. T., and Elveback, L. R. Trace Metals inHuman OsteogenicSarcoma. Mayo Clin. Proc., 47: 476-478, 1972.

34. Kaltenbach,T., and Egen,E. Beitragezum HistochemieNachwiesvonEisen, Kupfer und Zinc in der Menschlich an Leber unter besondererBeruchsichtigrung des Selberolfid-Verfahvens nach Tumor. Acta Histochem., 25: 329-359, 1968.

35. Kamamoto, Y., Makiura, S., Sugihara, S., Hiasa, Y., Arai, M., andIto, K. The Inhibitory Effect of Copperon DL-EthionineCarcinogenesis in Rats. Cancer Res., 33: 1129—I135, 1973.

36. Kew, M. C., and Mallett, R. C. HepaticZinc ConcentrationsinPrimary Cancerof the Liver. Brit. J. Cancer,29: 80-83, 1974.

37. Koslowski, J., Litwin, J., andSitniewski, S. A HistochemicalStudy ofGranulocyte Zinc Content in Cutaneous Neoplasia and in SkinReactions to Internal Malignancy. Acta Dermato-Venereol., 47:269-274,1967.

38. Lau, T. J., Hackett, R. L., and Sunderman, W. F., Jr. TheCarcinogenicity of Intravenous Nickel Carbonyl in Rats. Cancer Res.,32: 2253-2258, 1972.

39. Leach,R. M., Jr. Role of Manganesein MocopolysaccharideMetabolism. Federation Proc., 30: 991-994, 1971.

40. Levander, 0., and Morris, V. C. Interactions of Methionine, VitaminE andAntitoxidantsin SeleniumToxicity in the Rat. J. Nutr., 100:1111-1117,1970.

41. Lindeman, R. D., Bottomley, R. G., Cornelison, R. L., Jr., andJacobs, L. A. Influence of Acute Tissue Injury on Zinc Metabolism inMan. J. Lab. Clin. Med., 79:452-460, 1972.

42. Mautner, H. G., Chu, S. H., Jaffe, J. I., and Sartorilli, A. C. TheSynthesis and Antineoplastic Properties of Selenoguarine, Selenocytosine and Related Compounds. J. Med. Chem., 6: 36-39, 1967.

43. McBean, L. D., Dove, J. 1., Halsted, J. A., and Smith. J. C. ZincConcentration in Human Tissues. Am. J. Clin. Nutr., 25: 672-676,1972.

44. McGlashan, N. D. Zinc and Oesophageal Cancer. Lancet, 1: 578,1972.

45. McQuity, J. T., Jr., DeWys, W. D., Monaco, L., Strain, W. H., Rob,0. G., Apgar, J., and Poires,W. Inhibition of Tumor Growth inDietary Zinc Deficiency. Cancer Res., 30: I 38 1- I 390, 1970.

46. Melendez,L. V., Hunt, R. D., Daniel, M. D., Fraser,C. E. 0., Garcia,F. G., and Williamson,M. E. LethalReticulo-proliferativeDiseaseInduced in Cebus Albifrons Monkeys by Herpes Virus Saimiri. Intern.J. Cancer,6: 431-435,1970.

47. Moffitt, A. E., Jr., Dixon, J. R., Phipps, F. C., and Stokinger, H. E.The Effect of BenzpyrenePhenobarbitalandCarbon Tetrachloride onSubeellular Metal Distribution and Microsomal Enzyme Activator.CancerRes.,32:1148-1153,1973.

48. Mortazavi, S. H., Bani-Hashem, A., Mozafari, M., and Raffi, A.Value of Serum Copper Measurementsin Lymphomas and SeveralOther Malignancies.Cancer,29: 1193-1198, 1972.

49. Mulay, I. L., Roy, R., Knox, B. E., Suhr, N. H., and Delaney,W. E.Trace Metal Analysis of Cancerous and Non-Cancerous HumanTissues. J. Natl. Cancer Inst., 47: 1-13, 1971.

50. Nelson, A. A., Fitzhugh, 0. G., and Calvan, 0. Liver Tumorsfollowing Cirrhosis Caused by Selenium in Rats. Cancer Res., 3:230-236, 1943.

SI. Neubauer, 0. Arsenical Cancer: A Review. Brit. J. Cancer, 1:192-251,1947.

52. Oldficld, J. R., Allaway, W. H., Draper, H. H., Frost, D. V., Jensen,

3486 CANCER RESEARCH VOL. 35

on May 24, 2020. © 1975 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Trace Elements

L. S., Scott,M. L., andWright, P. L. (eds.),Seleniumin Nutrition.Washington, D. C.: National Academy of Sciences, 1971.

53. O'Leary, J. A., and Feldman, M. Serum Copper Alterations in GenitalCancer. Surg. Forum, 21: 411-412, 1970.

54. Olson, K. B., Heggen,G. E., and Edwards,C. F. Analysis of 5 TraceElements in Liver of Patients Dying of Cancer and Non-cancerousDisease. Cancer, 11: 554-561, 1958.

55. Petering, H. G., Buskirk, H. H., and Crim, J. A. The Effect of DietaryMineral Supplement on the Rat on the Antitumor Activity of3-Ethoxy-2-oxybutyraldehyde Bis(thiosemicarbazone). Cancer Res.,27: 1115—1121,1967.

56. Pfeilsticher, K. Spurenelemente in Organen und Urin bei Krebs. Z.KIm. Chem. Klin. Biochem., 3: 145-150, 1965.

57. Poires, W. J., Henzel, J. i-I., Rob, C. G., and Strain, W. H.Accelerations of Wound Healing in Man with Zinc Sulfate Given byMouth.Lancet,1:121-129,1967.

58. Poires, W. J., Henzel, J. H., Rob, C. G., and Strain, W. H.Accelerations of Healing with Zinc Sulfate. Ann. Surg., 165: 432-436,1967.

59. Poires, W. J., and Strain, W. H. Zinc and Wound Healing. in: A. S.Prasad (ed), Zinc Metabolism, pp. 378-391. Springfield, Ill.: CharlesC Thomas,Publisher,1966.

60. Poswillo, D. E., and Cohen, B. Inhibition ofCarcinogenesis by DietaryZinc. Nature, 231: 447-448, 1971.

61. Prasad,A. S., and Oberleas,D. Zinc Deficiency in Man. Lancet, 1:1520—1521,1973.

62. Prasad, A. S., Oberleas, D., Miller, E. R., and Luecke, R. W.Biochemical Effects of Zinc Deficiency: Changes in Activities ofZinc-dependent Enzymes and Ribonucleic Acid and DeoxyribonucleicAcid Content ofTissues. J. Lab. Clin. Med., 77: 144-152, 1971.

63. Rothrock, J. T., Pope, A. L., Ganther, H. E., Swanson, A. B.,Hafeman, D. G., and Hoekstra, W. G. Selenium: Biochemical Role asa Component ofGlutathione Peroxidase. Science, 28: 588-590, 1970.

64. Roy-Chowdhury, A. K., Muoney, J. I., and Reeves, A. L. TraceMetals in Asbestos Carcinogenesis. Arch. Environ. Health, 26:253—255,1972.

65. Sanstead, H. H., and Rinaldi, R. A. Impairment of DeoxyribonucleicAcid Synthesis by Dietary Zinc Deficiency in the Rat. J. CellularPhysiol., 73: 81-83, 1969.

66. Schwartz, A. E., Leddicotlo, G. W., Fink, R. W., and Friedman, E. W.Trace Elements in Normal and Malignant Human Breast Tissue.Surgery, 76: 325-329, 1974.

67. Shamberger, R. J. Relationship of Selenium to Cancer. I. InhibitoryEffect of Selenium on Carcinogenesis. J. Nail Cancer Inst., 44:931-936, 1970.

68. Shamberger, R. J., and Frost, D. V. Possible Inhibitory Effect ofSelenium on Human Cancer. Can. Med. Assoc. J., 100: 682, 1969.

69. Shamberger, R. J., Rukoven, E., Longfield, A. K., Tyko, S. A.,Deodhar,S., and Willis, C. E. Antioxidant andCancer. I. Seleniuminthe Blood of Normal and Cancer Patients.J. NatI. Cancer Inst., 50:863—870,1973.

70. Stanton, M. F., and Wrench, C. Mechanism of MesotheliomaInduction with Asbestos and Fibrous Glass. J. NatI. Cancer Inst., 48:797—821,1972.

71. Stocks, P., and Davies, R. I. Zinc and Copper Content of SoilsAssociated with the Incidence of Cancer of the Stomach and OtherOrgans. Brit. J. Cancer, 18: 14-24, 1964.

72. Stoeckle, J. D., and Mancuso, T. Beryllium Disease. Science, 183: 449,1974.

73. Sunderman, F. W., Jr. Inhibition of Induction of Benzpyrene Hydroxylase by Nickel Carbonyl. Cancer Res., 27: 950-955, 1967.

74. Sunderman, F. W., Jr. Atomic Absorption Spectrometry of TraceMetals in Clinical Pathology. Human Pathol., 4: 549-582, 1973.

75. Sunderman, F. W., and Sunderman, F. W., Jr. Implication of Nickelas a Pulmonary Carcinogen in Tobacco Smoke. Am. J. Clin. Pathol..35: 203-209, 1961.

76. Szmigielski, S., and Litwin, T. Histochemical Demonstration of Zincin Blood Granulocytes, a New Test in the Diagnosis of NeoplasticDiseases. Cancer, 17: 138 I - I 384, 1964.

77. Tani, P., and Kokkola, K. Serum Iron, Copper and Iron-bindingCapacity in Bronchogenic Pulmonary Carcinoma. Scand. J. Respirat.Disease, Suppl., 80: 121-128, 1972.

78. Tessmer, C. F., Hrgovcic, M., Brown, B. W., Wilbur, J., and Thomas,F. B. Serum Copper Correlations with Bone Marrow. Cancer, 29:173-179,1972.

79. Tessmer, C. F., Hrgovcic, M., Thomas, F. B., Fuller, L. M., andCastro, J. R. Serum Copper as an Index of Tumor Response toRadiotherapy. Ther. Rad., l@: 635-639, 1973.

80. Tessmer, C. F., Hrgovcic, M., Thomas, F. B., Wilbur, J., andMumford, D. M. Long Term Serum Copper Studies in AcuteLeukemia in Children. Cancer, 30: 358-365, 1972.

81. Tessmer, C. F., Hrgovcic, M., and Wilbur, J. Serum Copper inHodgkin's Disease in Children. Cancer, 31: 303-315, 1973.

82. Thiers, R. E. Contamination in Trace Element Analysis and ItsControl. Methods Biochem. Anal., 5: 273-335, 1957.

83. Tscherkes, L. A., Volgarev, M. N., and Aptekar, S. G. SeleniumCaused Tumors. Acta Unio Intern. Contra Cancrum, 19. 632-633,1963.

84. Tupper, R., Watts, R. W. E., and Wormall, A. The Incorporation ofZn' in Mammary Tumors and Some Other Tissuesof Mice AfterInjection of the Isotopes. Biochem. J., 59: 264-268, 1955.

85. Ulmer, D. D. Metals—From Privation to Pollution. Federation Proc.,32: 1758-1762,1973.

86. Valberg, L. S., Holt, J. M., and Szivelt, J. Determination of Calcium,Magnesium, Copper, and Zinc in Red Blood Cells by EmissionSpectrometry. Ann. Chem., 36: 790-792, 1966.

87. Van Giessen, G. J., Crim, J. A., Petering, D. H., and Petering, H. G.Effect of Heavy Metals on the In Vitro Cytotoxicity of 3-Ethoxy-2-Oxybutyraldehyde Bis (Thiosemicarbazone) and Related Compounds.J. Nail Cancer Inst., 51: 139-146, 1973.

88. Varsieck, J., Barbier, F., Speecko, A., and Hoste, J. Manganese,Copper and Zinc Concentrations in Serum and Packed Blood Cellsduring Acute Hepatitis, Chronic Hepatitis and Post-Hepatic Cirrhosis.Clin.Chem.,20,1141-1145,1974.

89. Wolff, H. Untersuchungen zun Pathophysiologie des Zinkstoffwechsels. KIm. Wochschr., 34: 409—418,1956.

90. Wright, E. B., and Dormandy, T. L. Liver Zinc in Carcinoma. Nature,237: 166,1972.

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