Download 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
The review considers trace elements including fluorine,
copper, manganese, zinc, cobalt, chromium, selenium,
molybdenum, tin, vanadium, silicon, and nickel from the
standpoint of their role as either inhibitory or causative
agents of cancer and also the possible use of their assay in
biological fluids as diagnostic or prognostic aids in patients
with cancer.
Introduction
The role of trace metals in cancer has been the subject of
conjecture, and reports of different authors are often
conflicting and contradictory.
A major reason for these
discrepancies is the difficulty in analyzing trace elements
and the problems that exist in collecting specimens without
contamination
(82). Trace elements are required in small
concentrations
as essential components of biological en
zyme systems or of structural portions of biologically active
constituents. They constitute, in toto, less than 0.01 % by
weight of the total body composition and those thus far
defined as essential in animal deficiency experiments include
iron, iodine, fluorine, copper, manganese, zinc, cobalt,
chromium,
selenium, molybdenum,
tin, vanadium, and
possibly silicon and nickel (20). The metals (all of the above
except idodine, fluorine, and selenium) play their most
important role as cofactors in enzymes. Iron is an important
constituent of succinate dehydrogenase as well as a part of
the heme of hemoglobin, myoglobin, and the cytochromes.
Zinc is involved in carbonic acid (carbonic anhydrase), and
in alcohol (alcohol dehydrogenase) formation, and in pro
teolysis (carboxypeptidase, leucine aminopeptidase, etc.)
(4). Copper is present in many enzymes involved in oxida
tion (tyrosinase, ceruloplasmin, amine oxidase, cytochrome
oxidase), and manganeseis a part of enzymesinvolved in
urea formation,
pyruvate metabolism,
and the galacto
transferase of connective tissue biosynthesis. In addition to
its role in vitamin
12,cobalt is also a cofactor of enzymes
involved in DNA biosynthesis and amino acid metabolism.
Molybdenum plays an important role in purine metabo
lism; selenium is related to glutathione peroxidase, an en
zyme 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 part
by USPHS Grant CA 08748from the National Cancer Institute.
jurious effects of hydrogen peroxide; and vanadium blocks
cholesterol biosynthesis.
In animal deficiency studies it has been determined that
selenium can prevent muscular dystrophy and liver necrosis
in rats and white muscle disease in cattle. Chromium is
needed for growth of rats and its deficiency leads to a
reduced life-span, corneal lesions, and interference with
insulin action producing a diabetic state with removal of
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
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
development of skeleton and feathers of young chicks, and
nickel is essential for the growth of wing and tail feathers
(20).
The effects of trace elements are related to concentration
and recorded observations range from a deficiency state, to
function as biologically essential components, to an unbal
ance when excess of one element interferes with the function
of another, to pharmacologically
active concentrations (i.e.,
zinc in healing), and finally to toxic and even life-threaten
ing concentrations
(85). The purpose of this review is to
consider the trace elements from the standpoint of both
their role in carcinogenesis and the possible use of their
assay in biological fluids as diagnostic or prognostic aids
in patients with cancer. Iron and iodide will not be
considered since they have been the subject of many reviews
and, although present in relatively small concentrations,
they are psychologically, if not physiologically, not “trace
elements. “
The review will not consider such elements as
arsenic 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 cancer
patients have been variable. Serum yields higher zinc levels
than does plasma, presumably due to platelet breakdown.
There is a diurnal variation in serum zinc concentrations,
and zinc values less than the fasting concentrations are
observed for 2 to 3 hr after the ingestion of food. In addition
there is a decline in zinc levels with increasing age and
women demonstrate
lower levels than men (5). Normal
RBC contain about 10 times the concentration of zinc seen
in serum, and about 30%ofserum zinc is bound to albumin.
Zinc is presumably transported
bound to a specific a2glycoprotein (22). Because of the possible variables in serum
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M. K. Schwartz
zinc levels, it has been suggested that RBC zinc concentra
related to cancer of the esophagus and stomach (44, 71).
Poswillo and Cohen (60) found that ingestion of zinc
tions may be a better indicator of zinc deficiency states.
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
leu
granulocytes of such patients (37, 76, 86). “Hypozincemia―carcinoma (12). Survival of mice with transplanted
is a nonspecific observation and decreased serum zinc levels kemia or an ascites carcinoma was also prolonged by the
deficiency (I 2). These effects were attributed to a zinc
have been found in cirrhosis, hepatitis (88), lung infections
deficiency interfering wuth DNA synthesis (65). Guthrie
including tuberculosis, myocardial infarction, renal insuffi
and Guthrie (22) found that injection of 0.05 ml of 4% zinc
ciency, diseases producing increased muscle metabolism,
acute tissue injury (41, 82), and pregnant women (61). chloride into the testes of Syrian hamsters produced embry
onal carcinomas (testicular teratoma) in 2 of 49 animals.
Steroid therapy, including administration of p.o. contra
Zinc metal powder injected into the trachea and pleura of
ceptives, also produces a hypozincemia (18, 19).
in the lungs and seminomas
Patients with cancer excrete as much as 3 times more zinc rats produced reticulosarcomas
in the testicles in 15% of the animals (17).
in their urine than do normal persons and in such patients
An important consideration for the cancer patient is the
the molybdenum excretion is decreased. Pfeilsticher (56)
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
patients, greatly accelerates
healing (25,
in prostatic cancer tissue than in normal prostate tissue, but postoperative
57—59).Zinc sulfate p.o. increased the healing rate of bed
they are increased in benign prostatic hypertrophy tissue
(23). Liver, kidney, or lung harboring metastasis has a sores and leg ulcers when the serum zinc concentration
before treatment was 110 zg/ 100 ml but not in patients with
higher zinc content than does the corresponding
normal
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
ase, may account for reports of its role in regeneration of rat
normal levels in serum.
liver (62).
Kew and Mallett (36) reported that in normal liver tissue
The exact role of zinc is unknown. Zinc binding may be
the zinc concentration is about 78 ±41 @g/g,wet weight;
related to cancerigenesis in the sense that the metals may
that of noncirrhotic liver tissue from patients with primary
liver cancer is about 75 ±3 1 @ig/g;cirrhotic liver tissue from effect catabolic or anabolic enzymes. Chvapil (6) has
may
these patients is about 45 ±23 zg/g, and the primary liver proposed that zinc is an integral part ofbiomembranes,
cancer itself is about I 8 ±7 @.tg/g.Low zinc levels have been control membrane integrity, and may be involved in the
stability of membranes and in lipid peroxidation-related
reported in hepatic metastases from a variety of sources
with greater than normal values in the liver harboring the injury. Zinc has been observed to function as a mitogen
of lymphocytes
in a
cancer. Olson et a!. (54) reported increased liver zinc inducing blastogen transformation
Phytohemag
concentrations
in patients with cancer, and McBean et a!. fashion similar to that of phytohemagglutinin.
(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
phosphodiesterase,
and its activating effect on membrane
disease have been reported to be similar to that of individu
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 ±49.8 .tg/g, dry weight, com
Copper is primarily found in serum (95%) as part of the
pared to 465.8 ± 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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TraceElements
ingested copper is rapidly converted in the liver to cerulo
plasmin. Cellular copper is primarily found in mitochon
dna, and the adult body contains about 100 to 150 mg with
the highest organ concentration in liver, kidney, heart,
brain, and pancreas. Only 10 to 60 zg of copper are excreted
in the urine each day.
The role of copper, hypocupremia, and elevated liver
copper concentrations in Wilson's disease are well docu
mented and the effects of copper toxicity have been clearly
described. Deficiency states have been reported in malab
sorption (kwashiorkor, sprue, celiac disease), marasmic
infants, infants with Mentes kinky hair syndrome, and
nephrotic syndrome. Elevations of serum copper have been
reported in multiple sclerosis, infection, myocardial infarc
tion, acute and chronic liver disease, and schizophrenia (74).
There is a relationship between serum copper and inflam
mation, and in some patients, but not all, there is a direct
correlation with C-reactive protein. In patients with lym
phomatous diseases the role of copper has been the subject
of considerable
investigation
(32, 48). Elevated serum
copper has also been reported following administration of
estrogens or thyroid and pituitary hormones and after
surgery (31).
In 6000 patients serum copper was correlated to other
biochemistry tests obtained on the SMA 12/60. There was
no definite correlation between serum copper and other
biochemical markers such as alkaline phosphatase, lactic
dehydrogenase,
and transaminase.
It was concluded that,
although serum copper elevations are not specific indicators
of particular disease, they are a relatively independent
parameter. In assessing serum copper in a pediatric popula
tion, it is important to keep in mind that there is a drop in
copper concentrations until the adult level is reached.
In a study of 236 patients with a variety of malignant
lymphomas (excluding Hodgkin's disease), Hrgovcic et a!.
(3 1) reported a significant difference in serum copper levels
related to disease activity. Levels were high in patients
before therapy and were lowered during successful therapy
with an observation of concentrations within normal levels
during remission. A recrudescence
of the levels was a
premonitor
of clinical relapse. The extent of elevation
appeared to be much greater in patients with generalized
disease compared to those with localized disease. There did
not appear to be any difference in the copper levels whether
the disease was lymphocytic, histocytic, mixed, or undif
ferentiated. The serum copper patterns were similar to
serum copper levels reported by these authors in 191 adult
patients with Hodgkin's disease (30). The elevations in
Hodgkin's disease were related to increases in ceruloplas
mm, whereas those in liver disease were attributed to inter
ference with the excretion of copper in the bile. In a study
of 28 patients with Hodgkin's disease, values between 71
and 131 ;Lg/ 100 ml were observed in 5 patients in corn
plete remission, and values between 172 to 426 sg/ 100 ml
were noted in 20 patients with active disease. Two other
patients with active disease exhibited normal values (69 to
133 @g/lOOml in 117 normal persons). Hypercupremia
was observed in 3 of 9 patients with reticulum cell sarcoma.
Serum copper has been evaluated as an index of tumor
response to radiotherapy (79). In Hodgkin's disease serum
copper determinations are useful indicators of the effec
tiveness of chemotherapeutic regimens used in obtaining
the 1st treatment response and then as an early indicator
of reactivation of disease. Elevations may occur 1 to 6
months before clinical evidence of relapse has occurred
(28). Similar serum copper levels have been observed in
children with Hodgkin's disease (81).
In patients with leukemia, normal values were observed in
12 pediatric patients with acute lymphocytic leukemia who
were in complete remission. In 8 patients with active
disease, increased percentages of bone marrow blast cells
were associated with abnormal serum copper concentrations
(78, 80). Similar observations were made in 265 pediatric
and 89 adult patients with acute lymphatic leukemia (29).
The development of tumors in mice after administration
of
Maloney murine rhabdomyosarcoma
virus is preceded by
an increase in serum copper as is the induction of reticulum
cell sarcoma-like lesions in marmosets by Herpes saimiri, or
the growth of Morris hepatoma after s.c. implantation in
rats (46).
Serum copper has also been found elevated in other forms
of cancer including bronchogenic carcinoma (77), squamous
cell carcinoma
of the larynx (1 1), cervical and other
gynecological cancer (53), bladder ( I ) and breast cancer,
(10) but not in prostate cancer. In lung cancers elevations
were found in 43 of 71 patients. A highly significant
correlation was reported between serum copper and the
sedimentation
rate. In squamous cell carcinoma of the
larynx, elevations were observed in I study in each of 10
patients but in another study in only 10 of 67 patients.
Higher copper concentrations
have also been found in
cancerous tissue more than in normal laryngeal tissue. In
cervical cancer and in bladder cancer the elevations are
related to the stage of the disease and decrease in response
to treatment. All of 23 patients with breast cancer demon
strated elevated serum copper levels (299 ±34 @g/100 ml)
compared to 20 normals (108 ± 10 @g/l®ml). In breast
tissue the copper concentration
in normal tissue ranged
from less than 30 @zg/g,wet weight, to 170 and 50 to 460
;zg/g in tumor tissue. In every case the concentration in the
tumor tissue was greater than the homologous normal tissue
(an average of 2.3 times greater). Copper concentrations in
pleural fluid of patients with cancer did not seem to differ
greatly from those in benign diseases. The concentrations in
63 patients with breast cancer ranged from 35 to 152 zg/l00
ml; in 28 lung cancer patients, 62 to 121 @ig/l00 ml; in 33
lymphoma patients, 57 to 150 mg/dl; and in 62 patients with
metastatic tumors, 41 to 177 mg/dl (14). The pleural fluid
copper levels were related to serum copper levels and to the
pleural fluid protein. An examination of normal adult tibia
and osteogenic sarcoma indicated a small but significant
difference in the copper levels. In the normal bone the
concentration was 6.6 sg/g, dry weight, and in osteogenic
sarcoma it was 8.6 sg/g, dry weight (33).
There are a few studies concerning the cancerigenic
effects of copper in animals. In rats the effects of DL-ethio
nine in inducing hepatoma can be inhibited by the addition
of 0.25% cupric acetate to the diet. The mechanism of this
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M. K. Schwartz
inhibition is not explained. Dietary copper has also been
observed to interfere with p-dimethylaminoazobenzene
liver
tumor induction (35). The cytotoxicity
of 3-ethoxy-2oxybutyraldehyde bis(thiosemicarbazone) is greatly en
hanced by the presence of trace amounts of copper. As little
as 0.4 ppm of cupric ion activated the drug against Walker
256 tumor cells. The conclusion of the authors was that the
copper chelate of the compound was the active material
(87). It has been observed that this drug is effective as an
antitumor agent in rats bearing tumors but is without effect
in animals on a copper-deficient diet (55).
Nickel
A variety of nickel compounds and salts have been shown
to be carcinogenic. The cancerigenesis is inversely related to
the solubility of these compounds, and the least soluble in
aqueous media appear to be the most carcinogenic. Nickel
carbonyl [Ni(CO)4J has been reported to be implicated in
cancer of the lung and nasal sinuses in industrial workers
and as a possible carcinogen in tobacco smoke ( 16, 75).
The parenteral administeration of Ni(CO)4 (0.4 mg nickel
per 100 g) at intervals of 2 or 4 weeks produced 19 tumors in
121 rats. The tumors included 6 undifferentiated sarcomas,
3 fibrosarcomas, 3 carcinomas, I hemangioendothelioma, I
leukemia, and 5 lymphomas. Nickel carbonyl has been
shown to inhibit enzyme induction of cortisone-induced
tryptophan
pyrrolase
and phenothiazine-induced
ben
zopyrene hydroxylase, as well as protein synthesis and RNA
synthesis, by means of interference with DNA-dependent
RNA polymerase (38).
Benzopyrene induction of benzopyrene hydroxylase in rat
lung is associated with an increase in the copper and
manganese content of the microsomal fraction of the cell,
and a decrease in the nickel and chromium content of this
fraction (47). Phenobarbital
also produces a nonspecific
increase in microsomal copper, manganese, and zinc. It was
postulated
that an early event in microsomal
enzyme
induction may be a redistribution ofendogenous
activity or
inhibitory metals. Administration of DDT is associated with
enzyme induction and an increase in hepatic copper (47).
Beryllium
In 1973 it was reported at a National Symposium on the
Current Status of Beryllium as an Occupational Hazard
that the rate of mortality from lung cancer in beryllium
plant employees who previously had had beryllium-induced
respiratory disease was statistically significantly higher than
in either all the plant employees or those who had not
experienced beryllium-induced
respiratory distress. Deaths
from cancer of the liver and pnacreas in these workers also
seemed 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 horses
whose hooves fell off after ingesting certain plants was a
3484
description of selenium poisoning (52). The ratio between
the 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 been
appreciated, and glutathione peroxidase, an enzyme essen
tial for peroxide protection, is selenium dependent (63).
Liver damage due to selenium ( 10 ppm as Na2SeO4) can be
prevented to some extent by addition of either DL-methio
nine, 0.50/g/ 100 ml, or DL-a-tocophenyl
acetate, 0.09
g/ 100 ml, but complete protection is gained by combination
treatment with methionine, 0.025 g/ 100 ml, and tocophenol,
0.05 g/ 100 ml. Other antioxidants such as N',N-diphenyl
p-phenylenediamineethoxyquin
(l,2-dihydroethoxy-2,2,4trimethylquinoline)
or butylhydroxytoluene also protected
against the effects of selenium (40).
Near toxic levels of selenium have been reported to
produce tumors in rats but other studies indicated that these
concentrations
of selenium created chronic toxic hepatitis
that resembled hyperplasia (26, 50, 83). In the early studies,
ingested selenium produced I I liver tumors in 53 animals
who survived 18 months, but the latter investigation mdi
cated that only hyperplastic lesions were found in the livers
of animals that lived more than 282 days.
Dietary selenium, presumably due to its antioxidant
properties, has been found to prevent occurrence of tumors
in animals fed or subjected to topically administered
carcinogens. Clayton and Bauman (7) were able to inhibit
butter yellow carcinogenesis in rats fed 5 ppm selenium, and
Mautner et a!. (42) found that selenopurines inhibited
lymphomas to a much greater extent that the nonconjugated
purines.
Shamberger et a!. (69) found that previous application of
sodium selenide, 0.0065 g/l00 ml, reduced the incidence of
carcinogenesis induced by topical application of 7,l2-di
methylbenzanthracene
and croton oil. Shamberger also re
ported a reduced incidence of 7,12-dimethylbenzanthra
cene-croton oil-induced papillomas in mice by dietary
administration of 1 ppm of selenium (67). In the mice
without selenium in the diet papillomas developed in 26 of
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
not known. Selenium is known to bind loosely to proteins
and is taken up rapidly by rapidly growing tumors. The
presence of selenium in the tumor cell may successfully
compete with the carcinogen for binding places of the
protein and thereby prevent cancerigenesis. Selenium has
also been shown to interfere with genetic processess in
barley and in Drosophila melanogaster (67). The protective
role of selenium in cancerigenesis is also supported by the
fact that there seem to be relationships between selenium
occurrence in soil and forage crops and the death rate from
cancer in the United States and Canada and between the
levels of selenium in blood and the human death rate from
cancer (68).
Trace Elements in Asbestos Cancerigenesis
Asbestos is the general term applied to a number of
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Trace Elements
fibrous silicates. Chrysolite and crocidolite appear to be
more active in inducing mesotheliomas than is amosite.
trations found in the early proliferative
Chrysolite, crocidolite, and brucite, the magnesium hydrox
higher manganese concentrations than does homologous
normal tissue (49). In 9 patients the normal tissue ranged
from 72 to 24 @g/g,whereas the malignant tissue ranged
from 10 to 55 @g/g,and in all cases the concentration of the
malignant tissue was greater than the normal. Manganese
was significantly higher in osteogenic sarcoma (6.6 ±4.4
ide outer layer of chrysolite, are carcinogenic in rats.
Asbestos carcinogens have been attributed to the physical
characteristics
of the fiber, contaminating
trace metals, or
organic materials on the fibers. The morphological role is
supported by findings that glass fragments of 0.06 to 3 mm
applied to pleura of rat lungs produced mesotheliomas in 12
to 18% of the animals (70).
Chromium,
lead, and nickel have been found in high
quantities in asbestos. In 1 sample of chrysolite, 5 mg of
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
fiber and additional nickel may be introduced during the
milling process. It has been suggested that the fiber serves
merely as a passive carrier of trace metals that are
responsible for the carcinogenesis. It has also been reported
that trace metals interfere with the metabolism of ben
zopyrene in the lung and maintain its presence in the cell for
longer periods of time (8, 15, 27, 64). The inhibition of
benzopyrene hydroxylase (aryl polycyclic hydroxylase) by
nickel has been proposed as a mechanism
for nickel
cancerigenesis (73).
Microsomal copper and manganese were increased and
microsomal
nickel and chromium
after the intratracheal
were decreased 72 hr
administration
of benzopyrene,
which produced a 6-fold increase in lung aryl hydrocarbon
hydroxylase activity. Lung microsomal copper increased
4-fold over control levels with no changes in the other
subcellular copper levels. There was 40% increase in micro
somal manganese, but a 40% decrease in nuclear man
ganese. The microsomal concentrations of nickel and
chromium were reduced to almost nondetectable levels. The
trace metals may play a role in the regulation of microsomal
enzyme activity in rat lung by altering the affinity of the
substrates for cytochrome P-450 or by altering the specific
ity of the substrate heme protein affinity for the active site
of the enzyme (47).
@
Manganese
Manganese is increased in serum of patients during the
active phase of acute icteric viral hepatitis. The mean value
in the patients is 2.32 ±0.96 ng/ml compared to 0.57 ±13
ng/ml in normals. The levels return toward normal in the
subsiding phase of the disease. In postnecrotic cirrhosis, the
serum but not the packed RBC manganese levels were also
significantly elevated. There is a significant correlation of
serum manganese and both bilirubin and aspartate amino
transferase in these patients. The increases were presumably
due to either release of hepatic manganese during parenchy
mal necrosis or decreased hepatobiliary excretion (88). The
liver has a relatively high concentration of manganese (1.5
± 2
@g/g,wet weight) and manganese
is primarily excreted
into the bile. Manganese concentrations in normal human
endometrium and in plasma are cyclic with highest concen
NOVEMBER
phase (Cyclic Days 6
to 8) (24). Malignant breast tissue demonstrates
;Lg/g)
than
in normal
tibia
(4.6
involved in glycosyltransferase
those needed for chondroitin
tive tissue metabolism (39).
± 1.6
@zg/g).
Manganese
much
is
and other enzymes including
sulfate synthesis and connec
Chromium
Chromium deficiency has been related to glucose metabo
lism and p.o. glucose causes increases in serum chromium in
normal persons but not in diabetics. The normal serum
concentration
is about 2.5 @g/ml. A precise role for
chromium in cancerigenesis has not been defined. It may
play a role in association with calcium in the stabilization of
nuclear nucleic acids (3).
Other Elements
There is little information available concerning the func
tion of other essential elements in cancer. Cobalt concentra
tions in osteogenic sarcoma are not significantly different
from those in normal bone. The level of cobalt in DNA
extracted from Walker 256 and sarcoma M.l cells is much
higher than that from normal rat liver. Tin levels have been
reported to be lower in some cancer tissues than in
homologous normal tissues. The significance of these find
ings is unknown.
References
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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
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Deficiency in Man. Lancet, 2: 1396, 1973.
5. Burr, R. G. Plasma-Zinc Levels. Lancet, I: 879, 1974.
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of Macromolecules
and Biological Membranes. Life Sci.. 13:
1041-1049,1973.
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8. Cralley, L. J. Electromotive Phenomenon in Metal and Mineral
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3487
Role of Trace Elements in Cancer
Morton K. Schwartz
Cancer Res 1975;35:3481-3487.
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