[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 “trace the heme of hemoglobin, myoglobin, and the cytochromes. elements. “The 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 NOVEMBER 1975 3481 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). “Hypozincemia―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 57—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 ±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 ±31 @ig/g;cirrhotic liver tissue from effect catabolic or anabolic enzymes. Chvapil (6) has these patients is about 45 ±23 zg/g, and the primary liver proposed that zinc is an integral part ofbiomembranes, may cancer itself is about I 8 ±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.