Zinc & Leukemia

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Zinc in Leukemia

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articles on zinc and leukemia

© by George Eby, Austin, Texas - December 1982.

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Introduction. RATIONALE FOR STUDY AND SUMMARY OF FINDINGS

 

 

It was noted that leukemic cells contain much less zinc than normal lymphocytes

which may be very important since zinc is vital for proper genetic and cellular

function.

 

Zinc metabolism deviations have been recognized in leukemia since 1949, but not

well understood, although zinc was used in the early 1950s as a therapeutic drug

in the treatment of leukemia.

 

Zinc may function therapeutically in leukemia by augmenting L-asparaginase in

killing leukemic cells (since a zinc deficiency may induce free asparagine), and

by stimulating cell mediated immunity. Zinc is believed to have been the only

nutrient that could have had a positive interaction with any of the

chemotherapeutic drugs in CCG protocol 161 regimen 2.

 

In the child's remission, zinc at 1-2 mg/pound of body weight was not observed

to cause an increase in lymphocyte count, but may have improved T-cell immune

function. Zinc may have aided in restoring normal growth while using

corticosteroids in a monthly pulse protocol.

 

Zinc is known to stimulate effector T-cell function and increase the number of

effector T-cells, even in leukemia, which may have aided in the destruction of

residual leukemic cells, through amplification of the plaque-forming cell

function of T-cells. Zinc is the body's only T-cell lymphocyte activator.

 

In studies to ascertain the practical role of zinc in related hematological

functions, zinc was found effective in increasing immunity to upper respiratory

viruses and infections in general in normal people and leukemic children,

management of Type I allergy and growth restoration in both normal and leukemic

children.

 

Therapy of the common cold with zinc yielded extremely rapid recoveries which

strongly suggested that a zinc-viral antigen complex was highly stimulatory to

interferon induction, and/or that the direct inhibition of rhinovirus by zinc

may be highly practical and effective in vivo.

 

Identical responses to zinc supplementation as an adjunct to standard treatment

occurred in about one dozen children when zinc treatment was started with

standard treatment between 1985 and 1997.

 

 

 

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I. A SEARCH FOR THE ETIOLOGY OF LEUKEMIA

 

 

Since many of the classical symptoms of leukemia were known to result from an

active disease, no rationale for their repeated study existed.

 

These classical symptoms include anemia, ease of bruising, fever, nightsweats,

splenic, liver and lymph gland enlargement, peripheral blasts, petechiae, bone

or joint pain, and hemorrhage.

 

 

 

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II. ZINC DEPLETION, THE COMMON DENOMINATOR

 

In a direct review of over 10,000 medical journal and clinical nutrition journal

articles published between 1976 and 1981, and review of computer searches of the

world medical literature, only zinc deficiency was found to have a role in the

occurrence of the seven pre-leukemic cells;

and by reversing the zinc deficiency killing leukemic cells, reducing

asparagine, and stimulating immunity to the leukemic cells.

 

Several other nutrients had roles in one or another symptom or function, but

only zinc was functional in each of them.

 

The role of zinc in leukemia and other activities is presented elsewhere within

this review. The full role of zinc in human nutrition is outside of the scope of

this review, and certain obvious roles of zinc such as its role in the male

reproduction system are purposefully omitted.

 

The granules of both basophils and mast cells also contain zinc ions (Ref. 2, p.

320). These ions stabilize the cell and prevent induced histamine and other

component release from mast cells if sufficiently available.

 

When released, zinc can contribute significantly to several immune reactions

described in other parts of this review.

 

It is believed that this effect of zinc is attributable to its action on the

cell membrane. It has been speculated that zinc may form mercaptides with thiol

groups of proteins, possibly linking to the phosphate moity of phospholipids or

interaction with carboxyl groups of sialic acid or proteins on plasma membranes,

resulting in a change of fluidity and stabilization of membranes (Ref. 3, p.

221; Ref. 71).

 

There are also several enzymes attached to the plasma membrane which control the

structure of the membrane, and the activation of these enzymes may be controlled

by zinc.

 

Adenosietriphosphatase (ATPase) and phospholipase A2 are known to be inhibited

by zinc, and this effect may explain immobilization of energy-dependent activity

of plasma membrane or increased integrity of the membrane structure (Ref. 3, p.

221).

 

Several receptors at the plasmatic membrane presumably function as a gate for

transmitting information to intracellular space. In the case of mast cells,

histamine-releasing agents seem to work through specific receptors at the

membrane. Masking of such receptor sites by membrane impermeable

Zn:8-hydroxyquinolone would thus explain the inhibition of the release reaction

(Ref. 3, pp. 221-222).

 

The role of Ca2+ in the function of cell microskeleton, represented by

microtubules and microfiliments, has been well documented. The contractile

elements of this system are in some way responsible for the mobility of

microorganelles and transport of granules to the membrane as well as

excitability of the plasma membrane itself.

 

Since zinc is known to compete with calcium, it may thereby inhibit this effect

of calcium (Ref. 3, pp. 221-222).

 

In addition to histamine's role as a mediator of Type I allergy, histamine also

has direct T-cell immunosuppressive aspects which are discussed elsewhere in

this review.

 

Inhibition of histamine release begins at about 10-6M concentration of zinc ions

(in humans) and is maximum at 10-4M concentration (10 times the normal 10-5M

concentration).

 

Zinc is released with histamine (Refs. 73,74) and may have an antiviral

function. Fifty mg zinc with each meal has been shown to be beneficial in the

treatment of allergic diseases (urticaria and erythema multiforme) where zinc

serum levels were low (65 mg dl)or 65% normal (Ref. 75).

 

It may very well be that the known zinc serum level reductions so often found in

leukemia are the cause of the severe allergy-like symptoms that precede

leukemia.

 

That they occur for as long as a year before leukemia occurs may result from a

powerful LEM-like reaction and possibly the leukemia inducing agent (virus?)

itself. Clearly, the release of histamine, unchecked by sufficient zinc ion

concentration is immunosuppressive.

 

VIRAL AND TUMORAL IMMUNITY

 

The T-cell lymphocyte response is the basis of cellular mediated immunity (CMI).

The CMI is vitally important in protection against virus, fungal and protozoan

infections, as well as against malignant and autoimmune disease. Effector

T-cells may be thought of as the immune system's " field commanders, " responsible

for the initiation and regulation of immune responses from other effector

T-cells, suppressor T-cells (including cytotoxic natural killer cells), ß cells,

and other white cells (Ref. 5).

 

They also interact with these cells in numerous immunological events designed to

present the best immune response. Antigen sensitized T-cells, upon second

exposure to the antigen, transform to an activated form, lymphoblasts, which can

directly lyse the antigen, or release soluble factors, lymphokines, which aid in

the destruction of the target cell or antigen. Interferon is released upon

exposure of T-cells to mitogens or specific antigens (Ref. 1, p. 302). Effector

and suppressor T-cells may be distinguished from each other through their

responses to mitogens.

 

A search was made for disease models having nutritional response to impaired

cell mediated immunity. Genetic causes of impaired cell mediated immunity and

congenital defects of CMI were reviewed and considered.

 

Vitamin A, B complex, and C, zinc, proteins and lithium were found to have a

role in the nutrition and function of the CMI (Refs. 6,7,8,9). In nutritional

deficiency, in general, there is often found significant immune system

impairment.

 

A reduced number of T-cells, an impairment of delayed hypersensitivity, an

impairment of mitogen and antigen induced lymphocyte DNA synthesis, a reduction

in soluble factors released, an increase in the number of null cells, a relative

decreases in the T-cell/ß-cell ratio (with ß-cells usually unchanged). increased

IgE, lowered IgG, IgA and IgM, unchanged phagocytosis, depressed serum

transferrin levels, decreased serum levels of most complement components and

other immune system alterations are observed in various states of malnutrition.

In mild under nutrition in children without growth retardation, alterations in

immunity function are less frequent (Ref. 4).

 

No specific disease model was found in this study wherein the normal CMI

response was depressed and could be normalized by restoration of a single

nutrient except for zinc. This includes scurvy and Vitamin C. In fact, scurvy

causes no characteristic change in the leukocytes at all (Ref. 1, p. 231).

However, it has recently been found that Vitamin C and hyperthermia produce a

modest enhancement of the immune response to influenza virus (Ref. 10).

 

Some examples: Thymic regrowth and cell mediated immune response after recovery

from protein-energy malnutrition was observed not to take place until after a

modest supplementation of zinc ( 2 mg zinc per kilogram of body weight was given

(Ref. 7).

 

Cell mediated immunity returns when zinc is administered in acrodermatitis

enteropathica (Refs. 11,12). Depressed cell mediated immunity returns when zinc

is administered in Down's Syndrome (Ref. 13). Down's Syndrome has a probability

of leukemia 30 times normal, when unsupplemented (Ref. 1, p. 290). It remains to

be determined if zinc will alter the leukemia rate in these children. In other

conditions such as general malnutrition and parenteral nutrition, zinc restores

depressed cell mediated immunity (Refs. 8,14,15,37).

 

Since the CMI response is also responsible for tumoral immunity, it becomes

important to understand the stimulating effect of zinc on CMI in the presence of

phytohemagglutinin (PHA) in vitro or antigens in vivo. Zinc has a specific

mitogenic effect on PHA stimulated T-cell lymphocytes (Refs. 3,6,16,17). PHA is

a specific effector T-cell mitogen vitro (Ref. 1, p. 307; Ref. 5). Lymphocytes

from rats fed a diet high in zinc were most susceptible to PHA transformation.

Within 3 days, zinc supplemented rats had twice the stimulation index of

controls. Within 5 days, it was three times control. By 7 days it has returned

to less than control (Ref. 6, p. 278).

 

This suggested that zinc accelerates the proliferative response of effector

T-cell lymphocytes which, in turn, could then accelerate and strengthen

responses of antigen sensitized cytotoxic killer cells from the suppressor

subset and other immune responses for the inactivation of viruses and tumors.

 

Plaque forming cell (PFC) responses to tumor cells in animals are significantly

lower in zinc deficiency. A decrease in the number of helper or effector

T-cells, or precursors of antibody forming cells or increased suppressor cell

activity may be responsible for this observation (Ref. 16).

 

Studies are needed to ascertain the role of supplemental zinc in reactivating

T-cell lymphocyte response to tumors. However, it is known that zinc increases

the number of effector T-cells.

 

It has been demonstrated that it is possible for the immune system to eliminate

large established tumors in mice by infusion of sensitized T-cells from immune

donors but only when the tumors grow in thymectimized and T-cell-depleted

recipients.

These and other similar findings strongly suggest that the failure of the immune

system to reject the immunogenic tumor is the result of the generation of

suppressor T-cells and not cytotoxic killer cells (Ref. 1.

 

Since the host immune response to a fetus is similar (or identical) to the host

immune response to a tumor (Ref. 19), an effect of zinc in stimulating effector

T-cell function against tumors (fetuses) may have already been observed in

animal pregnancy. Zinc supplements (100 mg zinc sulfate three times daily)

during the third trimester of pregnancy resulted in three pre-mature births and

one still-birth in four consecutive subjects (Ref. 20). Other recent studies

have presented data linking heightened suppressor cell function in human

pregnancy (a known zinc deficient state) to lowered PFC response and splenic

enlargement with suppressor cells. Similar PFC changes have been observed in

animals under conditions of tumor growth (Ref. 21).

 

Histamine is known to activate suppressor T-cells and to suppress the PHA

proliferative response of effector T-cells. A minimum of 2 hours contact with

histamine is required in order to activate suppressor cells. Maximum suppressor

activity occurs in 18-24 hours, and is not increased thereafter. The suppression

is dose-dependent. At a histamine concentration of 10-3M to 10-4M the

suppression is equivalent to that suppression obtainable with Con A (Ref. 42).

It is well known that histamine mediates the allergic responses encountered in

pre-leukemia as well as in other malignancies, atopic allergy, infections and

upper respiratory viral infections.

Consequently, zinc metabolism errors or gross zinc deficiency can directly

damage effector T-cell responses to tumors, and indirectly damage effector

T-cell responses to tumors through histamine inhibition of effector T-cells and

activation of suppressor T-cells.

 

A number of chemically induced or transplanted animal tumors have been

inhibited, prevented and/or eliminated by simultaneous administration of zinc.

Woster found that it was necessary to administer zinc within two days of the

administration of the tumor cells for zinc to be protective. Phillips and

Sheridan have demonstrated that zinc injected intraperitoneally prevented tumor

genesis in 50-70 percent of mice previously innoculated intraperitoneally with

certain leukemic cell lines.

 

Without zinc, all controls died from the same types of leukemic cells and dosage

(Ref. 22, p. 206). According to Phillips, either zinc potentiated effector

T-cell activity (specifically PFC function), or minimized the suppressor

response, or induced T-cell immune interferon, or directly poisoned these cells

or any combination thereof (Ref. 22,31).

 

Recent studies in human interferon production point out that lymphoblastic

transformations of T-cells is a necessary prerequisite to T-cell immune

interferon production (Ref. 23). Since other effector T-cell mitogens also

induce interferon (Ref. 43), the mitogenic property of zinc on effector T-cells

suggests that interferon production results.

 

Zinc without viral antigens has been demonstrated not to stimulate interferon

production (Ref. 31). Since there is a differential role for zinc between

antigen and mitogen induced lymphokine production (Ref. l67) it is suspected

that an antigen must be present before zinc can stimulate interferon production.

 

Several roles for zinc exist in the activation of T-cells. Zinc ions stimulate

DNA synthesis of lymphocytes within a few days; at this time approximately

10%-40% of cells are transformed into lymphoblasts.

 

Additionally zinc-8 hydroxyquinoline unsaturated complexes are stimulatory to

animal lymphocyte mitosis, even though it is cytoplasmic membrane impermeable.

Consequently at least two mechanisms exist for zinc to stimulate lymphocytes in

some animal models (Ref. 6, p. 278).

 

In humans, one protein, transferrin, is vital to CMI in that only transferrin

bound zinc is functional in the human T-cell lymphocyte. Since transferrin in

the humanis only 30% iron saturated, substantial zinc transport capacity for

immune function is normally available.

 

Clearly, a nutritional deficit that induces a loss or significant reduction in

transferrin synthesis would cause both anemia and primary immunodeficiency (Ref.

22). Interferon and transferrin concentrations are reduced in those nutritional

deficiencies, such as zinc, that interfere with protein synthesis (Ref. 66).

 

In leukemia, transferrin levels are often very low. Giving zinc raises the

transferrin serum level with a concurrent increase in lymphocyte transformation.

Adding transferrin by transfusion results in stable and normalized transferrin

serum levels but only when given in massive doses (20-30 mg/kg body weight/day)

over a 14-day period. Lesser doses are rapidly eliminated from the blood,

possibly by a LEM-like reaction where the liver removes zinc from the blood.

Again, lymphocyte transformation is increased.

 

In 1953 some remissions from acute lymphocytic leukemia occurred after giving

large doses of zinc and/or zinc transferrin, although the number of subjects was

too small to prove anything conclusive. During the course of treatment a

simultaneous tendency to normalization of the number of blood cells and

maturation of the peripheral blood also occurred (Ref. 44).

 

Unfortunately, T-cell lymphocyte count, activity and function in infants, early

childhood and in older people may be inadequate or absent. Alternatively, either

cytotoxic or suppressor subset functions might be too low or too high resulting

in imbalanced T-cell function, and predisposition to either immunodeficiency or

auto-immune disease (Ref. 5).

 

According to Robert Good, T-cell count and function change in humans after a

period of zinc deprivation resulting in thymic involution. A dramatic breakdown

in immunity follows, particularly helper T-cell and killer T-cell function as

well as plaque-forming (PFC) response to tumors. Other antibody-related changes

also occur.

 

The unique sensitivity of the human thymus to zinc depletion may be related to

the fact that terminal deoxyribonucleotidyl transferase is a zinc containing

enzyme which is only found in the thymus and immature thymocytes.

Zinc deficiency also causes other thymic related changes including a drastic

reduction in a hormone (FTS) needed in the differentiation of precursor cells

into Ø-positive lymphocytes (Ref. 46).

 

Zinc can be used to improve age-associated immune dysfunction. When oral zinc

supplementation (440 mg zinc sulfate) was given to institutionalized healthy

people over 70 years old, there was significant improvement in the number of

circulating T-cell lymphocytes, delayed cutaneous hypersensitivity reactions and

immunoglobulin G (IgG) antibody response. Zinc had no effect on the number of

total circulating leukocytes or lymphocytes or on the in vitro lymphocyte

response to three mitogens including PHA, Con A, or PWM) (Ref. 6. Malignant

disorders are often considered diseases of aging. It is highly probable that

administration of zinc to the elderly (or any age group) who demonstrate reduced

T-cell function will result in increased or even normalized resistance to tumor

formation.

 

Obesity as well as nutritional deficiency in humans can adversely affect CMI and

other immunological functions. In one test, zinc therapy for four weeks improved

immunological responses in the subjects (Ref. 70). Increased malignancy rates in

obesity have been observed. It seems probable that zinc can be effective in

reducing the malignancy rate in the obese population.

 

Since zinc is necessary for thymic function and effector T-cell function and

effector T-cell function is necessary for many other immune functions, it is now

somewhat clearer why zinc nutrition is important to immunological health. It is

noteworthy to observe that the new-born human infant receives 70-900 mmg zinc

per 100 gm colostrum, thus significantly changing the zinc/copper ratio and

activating the infant's primary immune system (Ref. 29, p. 30). Perhaps zinc is

truly nature's immune system switch.

 

Although zinc is necessary for interferon production, extremely high amounts of

zinc (10- 1M and above) result in the prevention of interferon release when

induced by the Sendai virus (Ref. 80). It is suggested that the zinc interferes

with the proteolytic cleavage of interferon before it is secreted. However, the

possibility of zinc inhibiting viral polypeptide cleavage was not discounted. No

change in interferon secretion was noted (either elevated or reduced) at zinc

ion concentrations less than 10-2M (Ref. 80).

 

BODY ODOR -- FREE ASPARAGINE?

 

On occasion a strong and offensive body odor is emitted from a person prior to

diagnosis of leukemia.

 

The odor is thought to be that of an accumulation of free asparagine which is an

essential amino acid for malignant cells by a nonessential amino acid for normal

cells.

 

In experiments to ascertain whether zinc played a role in nucleic acid

metabolism and protein synthesis, it was shown that for the microorganism

EUGLENA GRACILIS, zinc deficiency would result in a marked decrease in protein

and RNA content and an increase in free amino acids. The increase of amino acids

is largely accounted for by glutamine and asparagine. The accumulation of these

two amino acids suggest that they represent storage of excess nitrogen resulting

from impaired protein synthesis. Similar results have been observed in plants

(Ref. 6, p. 109).

 

Assuming that the molecular nature of unique biological activities is the same

in all biological species, then zinc deficiency could also result in an

accumulation of free asparagine in humans, and may explain the presence of high

levels of free asparagine in pre-leukemia and leukemia.

 

L-Asparagine synthetase has been shown to be responsible for the resistance to

L-Asparaginase in Acute Lymphocytic Leukemia. It is also present in many

experimental tumors and in the normal mammalian pancreas. In one experiment,

L-Asparagine synthetase was 90%-100% inhibited by zinc chloride at a 1 milliM

concentration in vitro.

 

Tests indicated that zinc interacted at the L-glutamine site on the enzyme. In

vivo zinc experiments failed to affect the concentration of L-Asparagine

although the test mice revealed necrotizing pancreatitis at a single dose rate

of 100 mg/kg or when given daily at a dose rate of 20 mg/kg (Ref. 4. Other

studies, primarily by Jerry Phillips, fail to substantiate the above statement

related to necrotizing pancreatitis at the stated doses (Ref. 31). This

important experiment needs to be repeated.

 

OTHER

 

Growth suppression, decreased weight, skin changes, mental lethargy, apathy,

depression, irritability, excessive fatigue, poor appetite, smell and taste

alterations, palpable liver and spleen, thymic atrophy, diarrhea, malabsorption,

steatorrhea and ophthalmic signs are a few of the other clinical manifestations

of zinc deficiency (Ref. 25; 26, p. 137). Most if not all of these symptoms have

been observed in pre leukemia. No more than one or two may be observed in any

one person or at any single time. In effect they can hardly be distinguished

from many other routine childhood illnesses, and are not direct evidence of zinc

deficiency.

 

The laboratory criteria for the diagnosis of zinc deficiency are not well

established either. The response to zinc therapy is probably the most reliable

index for making a diagnosis when considering the cause of such symptoms (Ref.

25). Zinc serum levels have not been shown to always be a reliable indicator of

zinc bioavailability. In fact, cases of acrodermatitis enteropathica, a lethal

zinc deficiency disease, have been found with much higher than normal zinc serum

levels, which returned to normal upon zinc supplementation (Ref. 11,27).

 

Symptoms found in zinc deficiency may also be caused by enzyme or cellular

malfunctions and by nucleic acid malfunctions. Over 90 enzymes have been

identified wherein zinc is a necessary constituent, with 45 being involved in

basic cellular reproduction (Ref. 46). Zinc functions in these enzymes by

maintaining spatial and configurational relationships (Ref. 26, p. 136). A

number of these enzymes such as alkaline phosphatase are involved in cellular

growth and are sensitive to zinc deficiency.

 

A few examples of zinc enzymes include: alcohol dehydrogenase, RNA polymerase,

DNA polymerase, alkaline phosphatase, carboxypeptidase A and B, dipeptidase,

aldolase, carbonic anhydrase, pyruvate carboxylase, and superoxide dismutase

(Ref. 3,6,15).

 

The precise relation of zinc to zinc deficiency symptoms remains to be

determined in most cases.

 

Growth related problems and fatigue could be related to the role of zinc in

protein synthesis, enzymes, and absorption (Ref. 15).

 

Mental and emotional problems could be related to zinc's role with histamine as

a neurotransmitter in the hippocampusmossy fiber structure of the brain (Ref.

29, p. 10). A palpable spleen might be related to zinc deficiency induced

increase in spleen seeking suppressor T-cell lymphocytes (Ref. 21).

 

Thymic atrophy could result due to the basic nutritional need for zinc by the

thymus (Ref. 7,46). Zinc is a functional part of the retina and is helpful in

treating cataracts of the elderly (Ref. 20).

 

Acne and other skin problems can be a zinc deficiency. Zinc is very helpful in

alleviating acne. Diaper rash often dramatically responds to zinc oxide lotion

(Ref. 20).

 

As more information about the clinical hallmarks of the zinc deficiency syndrome

is understood, the following are currently believed to be markers of zinc

deficiency: hypozincemia, iron deficiency anemia, hepatosplenomegaly, growth

retardation, arrested sexual maturation, partial adrenal insufficiency,

anorexia, dryness and hyper pigmentation of the skin, impaired taste and smell

acuity, delayed wound healing, sub optimal growth, poor appetite, pica, impaired

immune response. Diseases that are known to be associated with zinc deficiency

include malignancy and many other diseases (Ref. 7.

 

 

 

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III. ZINC DEPLETION, A STAGE FOR LEUKEMIA?

 

The role of zinc deficiency or improper zinc metabolism has been established as

possibly being causal in the conditions found prior to the actual development of

ALL, and suggests that zinc depletion may present a stage for leukemia, by

decreasing natural resistance to leukemia, by increasing the amount of free

asparagine, by increasing corticosteroid levels, and by allowing lymphocyte

genetic requirements for zinc to go unmet. Zinc deficiency in the leukemic

process itself can also be demonstrated.

 

ZINC CONTENT OF LEUKEMIC BLOOD

 

Leukemic cells contain only about 10% of the zinc contained in normal

lymphocytes (Ref. 1, p. 201). Plasma zinc concentrations are lower and plasma

copper concentrations are higher in children with untreated ALL than in the same

children after successful treatment or healthy children (Ref. 22,79). Zinc

transferrin is also low in many cases of leukemia (Ref. 44).

 

In one case of acute myelogeneous leukemia, zinc deficiency was so severe that

acquired acrodermatitis enteropathica developed (Ref. 30). In several cases of

ALL, zinc deficiency symptoms developed. Remarkably rapid elimination of zinc

deficiency symptoms and greatly increased tolerance to the chemotherapy occurred

with zinc (Ref. 62).

 

The DNA of CCRF-CEM human leukemia cells contain one-fourth of the zinc of

normal lymphocyte DNA. RNA from leukemic cells, however, contained nearly four

times the zinc of control RNA. Histone, from leukemic cells, which is known to

be involved in the regulation of gene expression, only contain one-fourth of the

zinc content as is contained in control histone.

 

Consequently, zinc depleted histone fractions could alter the interaction of

histones with DNA and as a consequence alter gene activity (Ref. 22, p. 204).

The nucleus of human chronic lymphocytic leukemia cells contain only one-third

the zinc of normal cells. The cytoplasm of human chronic lymphocytic leukemia

cells contain only one-third to one-fifth the zinc of normal cells.

 

Phillips found that leukemic lymphocytes incorporate transferrin bound zinc more

slowly and to a lesser extent than do normal lymphocytes. In addition, he found

that normal lymphocytes respond to increased intracellular zinc by synthesizing

a low molecular weight protein, possibly a metallothionein, while lymphocytes

from donors with chronic lymphocytic leukemia fail to synthesize this

intracellular zinc-binding protein (Ref. 22, p. 204).

 

It is well known that excessive zinc excretion and low level of serum zinc occur

in leukemia.

 

Zinc is necessary for proper regulation of prostaglandins as well as being

antagonistic to calcium.

 

In leukemia, and malignancy in general, cellular prostaglandin levels are

distorted resulting in cell membrane fluidity, rigidity or other functional

alterations. Calcium metabolism is unregulated, and no control over cytoplasm

calcium can be established thus resulting in undesired cellular division.

 

These differences along with impaired primary immune functions and other

biological activities are suggested to be reversible or controllable when

certain nutrients including zinc and gamma linolinic acid necessary for

prostaglandin and calcium regulation are supplemented in a sufficient amount and

in a biochemically available form (Ref. 72,73). The only known exogenous source

of gamma linolinic acid is the evening primrose oil.

 

GENETICS AND ZINC

 

Zinc is necessary for all growth. In is absence all growth, including malignant

growth, is not possible (Ref. 63).

 

As early as 1949, differences in zinc metabolism of normal and leukemic

lymphocytes first gave rise to the postulate by Vallee and Gibson that the

disturbance of a zinc-dependent enzyme is critical in the patho-physiology of

myelogenous and lymphatic leukemia as well as lymphoma, Hodgkin's disease and

multiple myeloma (Ref. 6,63).

 

Data obtained since 1949 bear out the 1949 postulate that zinc is involved in

nucleic acid metabolism and that zinc deficiency bears importantly on the

lesions observed in leukemia and other conditions (Ref. 6,63).

 

Experiments using ethylenediamine tetraacetate (EDTA) and other metal chelators

to chelate metals within DNA and DNA polymerase result in functional inhibition

of their activity which can be reversed only by adding Zn2+ in the growth

medium. The same results occur for terminal deoxynucleotidyl transferase,

DNA-dependent RNA polymerase and thimidine kinase from several species (Ref. 6,

p. 246; Ref. 63).

 

Direct evidence that the RNA-dependent DNA polymerase--a reverse

transcriptase--from avian myeloblastosis virus is a zinc metalloenzyme has been

obtained.

 

Zinc is the only mineral present in this enzyme (Ref. 3, p. 119; Ref. 64,65).

Inhibition of RNA-dependent DNA polymerase by zinc chelation brings about both

an instantaneous reversible inhibition and a time-dependent irreversible

inhibition (Ref. 6, p. 247). Zinc also regulates the activity of RNase, thus the

catabolism of RNA also appears to be zinc dependent (Ref. 3, p. 223).

 

Studies such as these establish the importance of the role of zinc in the

formation of DNA from RNA templates and extend previous findings that zinc is

necessary in the formation of RNA and DNA from DNA templates.

 

It is still not clear at all why zinc deficiency in genetic material causes such

molecular instability and dysfunction. There must be a relationship between zinc

deprivation and the malfunction of molecular systems based upon zinc

metalloenzymes (Ref. 6, p. 247).

 

In terms of enzyme sensitivity to zinc deficiency three enzymes -- alkaline

phosphatase, carboxydeptidase and thimidine kinase -- appear to be most

sensitive to zinc restriction in that their activities are affected adversely

within three to six days of institution of a zinc-deficient diet in experimental

animals (Ref. 3, p. 223).

 

Additionally, it has been demonstrated that zinc may be necessary for all phases

of cell growth. Zinc was required for cells to pass from the G1 phase into S,

from S to G2 and from G2 to mitosis (Ref. 3, pp. 115,217; Ref. 22, p. 205). It

is tempting to suggest that the proliferation of blasts in leukemia is solely

due to those cells being stuck in an early stage of development simply due to an

intracellular deficiency of zinc or zinc metabolism errors. However, in zinc

deprived rats the mast cell population of the tibia bone marrow became

increasingly higher than in controls.

 

It was also noted that zinc deficiency was responsible for the accumulation of

mast cells which were incapable of completing their maturation. In view of the

general growth depressing effects of zinc deficiency, it is difficult to imagine

the accumulation of mast cells in the bone marrow as the result of any known

growth stimulating phenomena. It was suggested as being possible to consider

zinc as a factor in the differentiation and release of the mast cells (Ref. 32).

 

Upon consideration of the human leukocyte antigen (HLA) system, the amelioration

of some diseases related to A1 and A2 have been demonstrated to be possible with

zinc.

 

 

Hayfever, and asthma (A1) and primary immunodeficiency (A2) can be ameliorated

by zinc when supplemented at the rate of 1-2 mg/pound/day . Recurrent Herpes

(A1) can be eliminated with topical zinc application.

 

If the genetic markers A1 and A2 denote a genetic need for increased dietary

zinc, then a number of other diverse HLA-A1 and A2 associated diseases (and

perhaps A3 and A10 diseases) might be ameliorated by zinc in much the same way

as pernicious anemia (B7) can be ameliorated by supplemental Vitamin B-12.

 

 

 

--

 

IV. NUTRIENT / CHEMOTHERAPY INTERACTIONS

 

As stated in Part I, a major reason for conducting this review was to determine

if any supplemental nutrient could positively influence the chemotherapeutic

agents used in CCG protocol 161 regimen 2. In this protocol, predisone,

vincristine, L-asparaginase, and intrathecal methotrexate are used for remission

induction followed by 2400 rads cranial radiation. Maintenance therapy calls for

use of vincristine and predisone on a monthly " pulse " basis, methotrexate weekly

and 6-mercaptopurine daily.

 

This protocol results in the depletion or inactivation of niacin, vitamins B-6,

C, D, and folic acid, as well as zinc, calcium, potassium and nitrogen. Of these

only folic acid is known to be intentionally depleted. Replacement of the other

nutrients may be beneficial to normal health, however only replacement of zinc

had even a theoretical possibility of influencing the performance of any of the

drugs used in this protocol, according to the literature reviewed.

 

ZINC/L-ASPARAGINASE

 

Zinc may be important as a dietary supplement at the rate of 1 - 1 1/2 milligram

zinc per pound of body weight in the treatment of ALL using protocols containing

L-asparaginase.

 

L-asparaginase contains the enzyme L-asparagine amidohydrolase which destroys

the amino acid asparagine. Leukemic cells are dependent upon an exogenous source

of asparagine for survival.

 

Normal cells, however, are able to synthesize asparagine and are thus affected

less by the rapid depletion produced by L-asparaginase. Depletion of asparagine

is a unique approach to therapy of ALL based upon a clear metabolic difference

between leukemic lymphocytes and normal lymphocytes (Ref. 34).

 

Linus Pauling writes in his book " VITAMIN C AND CANCER " about L-asparaginase:

" Theoretically the perfect anti-cancer drug, exploiting one clear biochemical

dissimilarity between normal and malignant cells. "

 

It has been demonstrated that zinc deficiency in bacteria and plants produces

accumulations of the free amino acid asparagine, which is believed to represent

storage of excess nitrogen resulting from impaired protein synthesis (Ref. 6).

 

Since many similarities at the molecular level exist between the species; it is

reasonable to suggest, at least in the absence of clear proof to the contrary,

that zinc deficiency induces free asparagine accumulation in human tissue.

 

Zinc deficiency is known to exist in leukemia.

 

The result is that this mineral deficiency, theoretically at least, competes

with L-asparaginase by stimulating L-asparagine synthetase thus replenishing

free asparagine. L-asparaginase is only effective when new asparagine is not

being released, or is being released at a rate commensurate with the dose,

frequency and duration of therapy with L-asparaginase.

 

Consequently, the supplementation of zinc should theoretically improve the

effectiveness of L-asparaginase in the management of malignant disorders even

though in vivo animal studies disagree (Ref. l48).

 

In the case of the child with ALL where 50 mg. of zinc was given daily and

coterminous with L-asparaginase, bone marrow blast count went from 95+% to an

observed count of zero blasts in less than 14 days. This is the only known

humans case of augmentation of L-asparaginase with zinc.

 

Since bone marrow improvements normally obtained by 85-90% of patients with ALL

on similar protocols still contain 3-5% blasts after 30 days in a M-1 remission,

these results, as far as can be determined, are completely unique in the

management of ALL. It is also significant since the rate in which a remission is

obtained, as well as the reduction in blast count, has been demonstrated to be

related to the propensity to relapse.

 

L-asparaginase has been observed to be highly toxic to the liver and capable of

inducing anaphylactic shock (Ref. 34). Zinc, to the contrary, has been shown to

have a protective influence from toxic substances, such as carbon tetrachloride,

on the liver and reduces or prevents anaphylactic shock through its mast cell

regulatory role in Type I allergy (Ref. 3, p. 221) and its stabilizing effect on

all cell plasma membranes.

 

No adverse reactions of any kind were noted in the first test of zinc as an

adjunct to L-asparaginase in the 3-year-old girl. Additionally, in the absence

of information in the literature to indicate harm by zinc, other tests of zinc

in the amplification of the effectiveness of L-asparaginase seem both reasonable

and necessary, if not given in great excess in order to eliminate or minimize

pancreatic injury.

 

NOTE: Consider L-asparaginase as " a mop to pick up asparagine from a leaky

faucet, while zinc turns off the faucet! " This combination in some form is

probably the cure for all cancers, although tumor death products may be toxic to

normal cells.

 

ZINC/PREDISONE

 

The action of predisone against leukemic lymphocytes involves the diminution of

glucose and amino acid transport into the cell, phosphorylation and thymidine

incorporation. So long as the cell line retains the cytoplasmic receptors for

glucocorticoids, the cell is susceptible to cytolysis in response to steroids

(Ref. 1, p. 1652). Corticosteroids increase urinary excretion of zinc and

decrease serum zinc (Ref. 26, p. 461) (Important!) Hyperfunction of the adrenal

cortex, with a release of cortisone accompanies zinc deficiency (Ref. 26, pp.

137,670). It is known that catabolism due to infection results in glucocorticoid

release and negative zinc balances (Ref. 26, p. 697). In protein-energy

malnutrition of children, thymic atrophy of stress is believed to be mediated by

high levels of circulating corticosteroids.

 

Zinc supplementation causes thymic regrowth in children recovering from

protein-energy malnutrition, whereas a normal high energy diet does not cause

thymic regrowth. Altering the corticosteroid/zinc relationship by supplementing

zinc relieved cell mediated immunity and humoral immunity problems in these

children, as zinc also stimulates both lymphocyte function and cell mediated

immunity (Ref. 7). Excessive zinc excretion occurs in leukemia (Ref. 47)

suggesting high corticosteroid levels and consequent immunosuppression.

 

In the case of the child who was administered zinc in conjunction with

predisone, no adverse reactions were encountered. Total white blood cell count

averaged 4000/mm3 and varied between 2000/mm3 and 7000/mm3 on infrequent

occasions.

 

Absolute lymphocyte count averaged 1400/mm3 until chemotherapy was increased due

to weight and height gain. Afterwards, ALC remained at 1000/mm3 or less.

Moonface appearance and obesity normally found with use of predisone were

absent. Immunity to diseases appeared normal in that the incidence of infection

became much lower after initiation of chemotherapy with zinc than during an

equivalent period prior to diagnosis. Atypical or activated lymphocytes were

noted in 12% of the bi-weekly blood tests. Growth was accelerated after

initiation of chemotherapy and zinc. A " catch-up " growth occurred from

preleukemic height and weight of 28% and 5% respectively to 50% and 50%

respectively after one year of treatment for ALL and use of zinc throughout the

third year, growth has remained at the 50% level for both height and weight with

only minor variations. In general the child enjoys excellent health and is very

strong.

 

In studying the immunostimulatory effect of zinc in patients with ALL in Poland,

researchers in 1978 added to the above observations. They found that, with drug

protocols very similar to CCG 161 that the effect of zinc was statistically

significant in enhancing T-cell mediated immunity, raising TEa5' percentage from

22.3 to 32.4 and absolute number of TEt60' from 338.8 to 517.2. No change in

IgG, IgA, IgM or total gamma globulins occurred. A slight decrease in

granulocyte count was the only adverse side effect noted. And it was not

considered statistically significant (Ref. 45).

 

Dental caries are predicted in zinc deficiency (Ref. 35). Since zinc deficiency

is often caused by use of predisone it is often found that dental caries

accompany ALL while undergoing treatment with predisone. In this case, no dental

caries formed, and dental health remained excellent, with 4 adult teeth forming

normally within the 3 years of treatment.

 

Bone marrow blast count has remained completely stable at 0.2% for three years

of therapy. During a one-month period after 24 months of therapy when therapy

was discontinued in order to administer chicken-pox vaccine, bone marrow blast

count only rose to 2%, and then returned to 0.2% upon resumption of

chemotherapy.

 

 

 

--

 

V. ZINC AS A VIRUS, AND RNA TUMOR VIRUS REPLICATION INHIBITOR

 

Experiments as early as 1973 by Bruce Korant have clearly demonstrated the

ability of zinc to act as a replication inhibitor for certain viruses. In the

rhinoviruses, zinc's effects are to block polypeptide cleavage. Addition of only

0.2mM zinc prevents post-translational cleavages and causes the accumulation of

a set of large precursor polypeptides.

 

Different cleavages were sensitive to different concentrations of zinc, and

progressively larger polypeptides could be accumulated by increasing the zinc

concentration. The addition of zinc at any time during viral replication

immediately inhibited further formation of infectious virons.

 

A number of other metals were also tested but only zinc displayed antiviral

activity in non-toxic concentrations. Eight out of nine rhinoviruses tested were

sensitive to zinc at 0.1mM concentrations. Only rhinovirus type 5 was resistant

(Ref. 6, 49).

 

Added zinc is bound to capsids of rhinoviruses and prevents them from forming

crystals. Zinc complexes with rhinovirus coat proteins and alters them so that

they cannot function as substrates for proteases or as reactants in the assembly

of virus particles (Ref. 50). The zinc ion is an inhibitor of virus production

and blocks protein cleavage of rhinovirus, enterovirus, and cardiovirus

precursors. Zinc ion blocks viral maturation of coxsackievirus. If zinc ions

were present at the start of rhinovirus infection (in vitro) the virus could do

little harm to cellular translation, thus host protein synthesis was spared if

viral proteins were not synthesized and normally processed (Ref. 51, pp.

149-173).

 

Many other viruses, including Herpes Simplex 1 and 2, encephalomyocarditis,

foot-and-mouth, enterovirus 70, vaccinia and some other viruses have also been

demonstrated in vitro and IN VIVO to be highly susceptible to destruction by

zinc at non-toxic levels (Refs. 52,53,54,55,57,57,58,59,60,61,81).

 

Korant, in addition, indicates that recent evidence for polypeptide cleavages

during the replication of bacteriophages, and many animal viruses including RNA

tumor viruses suggests a role for protease inhibitors, including zinc, in

blocking certain stages of replication of many viruses (Ref. 49).

 

Observing that zinc inhibits the formation of tumors in animals and kills human

leukemia (ALL) cells with other metal containing drugs such as CIS-platinum it

is plausible to suggest that these cells were driven by RNA-tumor viruses that

were controllable by zinc.

 

It is well known that viruses cause immunosuppression of their host in order for

them to survive. Perhaps the RNA tumor virus causes the long term depletion of

serum zinc in a manner similar to that resulting from bacterial infections or

endotoxin reactions involving LEM and the liver.

 

If that occurs, zinc depletion could result in long lasting immunosuppression

favorable to the survival of zinc intolerant viruses such as the proposed

RNA-tumor viruses. Fever is often associated with pre leukemia, and may indicate

a period of time consistent with LEM production as a precursor event to frank

leukemia.

 

Administration of aspirin at the time of this type of fever could stimulate

viral proliferation through increased immunosuppression, and could theoretically

promote leukemia.

 

Additional evidence has been acquired that zinc can control virus activated

tumor cells in that SV40-transformed human cells fail to grow in zinc

concentrations which permit normal human fibroblasts to proliferate (2-3 x

10-4M. The only difference between the cells was viral infection by an oncogenic

virus (Ref. 76).

 

Structural protein synthesis in the avian myeloblastosis virus have been shown

to be preventable by exposure of intact cells to 10mM (10-2M) concentrations of

zinc ions (Ref. 81) which is 100 times the concentrations necessary for control

of rhinoviruses.

 

 

 

--

 

VI. ZINC IN RELATED ACTIVITIES

 

Zinc is a vital constituent of red blood cells. Red blood cells contain 6 to 8

times the amount of zinc as blood plasma, which is around 100 mg/dl

(microgram/deciliter) (Ref. 16, p. 136). Most (75%-85%) of zinc in the blood is

associated with carbonic anhydrase of the erythocytes (Ref. 20, p. 61).

 

Zinc inhibits the formation and transformation of red blood cells into ghosts by

certain hemolytic reactions of the complement system (C-9) (Ref. 36), while most

zinc in cells is used to stabilize cell plasma membranes against viral

infection, toxins, amd complement.

 

Only platelets in the human require more zinc than mast cells or basophils (Ref.

6).

 

White blood cells contain up to 25 times the amount of zinc in the serum. Mast

cells and basophils contain extremely high amounts of zinc, being found in

granules with histamine.

 

Zinc inhibits macrophage mobility and phagocyte activity yet potentiates

macrophage viability. Zinc deficiency results in maximum macrophage mobility.

 

The effects are reversible and are believed to be due to a role of zinc on the

cell's membrane (Ref. 6, p. 271). The overall regulatory control of zinc blood

level is by the liver. Certain soluble factors, called leukocytic endogenous

mediators (LEM), are released by activated leukocytes or macrophages during an

acute inflammation of a bacterial origin or endotoxemia (Ref. 6, p. 93). They

cause a sequestering of plasma zinc and iron by the liver within hours,

accompanied by a potentiation of phagocytic function even when zinc is given at

the 1-2 mg zinc/pound rates. An endogenous pyrogen (EP) is also released by

phagocytizing white cells at the same time with a resultant increase in body

temperature (Ref. 3, p. 99). Hyperthermia has been shown to potentiate the

immune response (Ref. 10). It may be that the sequestering of zinc by the liver

for protracted periods in bacterial infections could result in thymic atrophy

and diminished T-cell function and count.

 

A significant fall in plasma zinc levels is noted in the third trimester of

human pregnancy (Ref. 20, p. 63). Similar plasma zinc level reductions occur in

malignant disorders. A triple purpose may be served by these changes: (1) fetal

or tumoral uptake of zinc occurs, (2) diminished cell mediated immunity to the

fetus or tumor (particularly PFC) occurs, and (3) leukocyte mobility enhancement

occurs (Refs. 19,21).

 

Zinc may be sequestered by tumors from body stores, primarily the liver and

bone, to fulfill their metabolic needs (Ref. 22, pp. 205-207). A consequent and

deepened immunosuppression may occur if accompanied by an inadequate dietary

intake of zinc. Tumor growth rate has not yet been shown to be accelerated when

zinc is supplemented sufficiently to meet other body requirements such as T-cell

and thymic requirements.

 

It has long been known that intestinal zinc and iron absorption is reduced in

bacterial infections and endotoxemia presumably to simplify the function of the

liver in starving the bacteria. Intestinal zinc absorption is enhanced in many

but not all viral infections, presumably to impede viral growth.

 

Zinc aids in Vitamin A absorption. Vitamin A deficiency has been liked to

malignant disorders. Could increased zinc intake in the general population aid

in raising Vitamin A serum levels and reduce the cancer rate?

 

 

 

--

 

VII. SOURCES OF ZINC DEFICIENCY

 

Zinc as a trace mineral is second only to iron in abundance in humans. Its role

in human metabolism is not yet totally known. Even the mechanism of zinc

absorption is poorly understood. Zinc deficiency to the T-cell lymphocyte system

and thymus may occur from a number of sources including inadequate dietary

intake, faulty absorption across the intestinal mucosal membrane, inadequate or

faulty albumen binding, inadequate cellular uptake, competition from other

metals such as calcium, dietary chelation by phylates, from whole wheat and

other dietary fiber, excessive soy bean intake, diarrhea, inadequate pancreatic

function, faulty transferrin synthesis, and loss through catabolism from stress

and infection (Refs. 3,6,15).

 

Low consumption of animal protein, geophagia, parasitic infestation, hemolysis,

blood loss, high intake of dietary fiber, alcoholism, liver disease,

malabsorption, renal diseases, burns, pregnancy, oral contraceptives,

penicillamine therapy, poor appetite, chronic debilitation, Crohn's disease,

cystic fibrosis, sickle cell anemia, malignancy, sweating, excessive consumption

of food products process with EDTA or other metal chelators (used to prevent

spoilage), poisoning by heavy metals such as lead and cadmium, and starvation

are often accompanied by zinc deficiency (Refs. 3,6,15). In many other diseases

zinc deficiency occurs for various reasons. Some are mentioned elsewhere in this

report.

 

One writer found that it was difficult to find a stimulus to zinc absorption.

Zinc is primarily absorbed and excreted through the intestines (Ref. 6).

 

Increased urinary zinc excretion occurs as a consequence of a number of

conditions including leukemia and other malignancies, starvation and surgery. It

has been suggested that urinary zinc may provide an index by which to measure

muscle catabolism (Ref. 26, p. 137).

 

Surgery has been shown to occasionally cause a permanent disturbance to zinc

metabolism, unless 1 to 5 mg zinc/pound body weight is administered during and

after (several days to several months) healing process. (Ref. 46).

 

In the case of growing children, competition for zinc is so intense and the

opportunities for zinc deficiency so numerous that normal dietary zinc intake

may be quite inadequate to supply all of the growing child's needs (Ref. 3, p.

202; Ref. 6, p. 30).

 

The result being that faulty cell mediated immunity and excessive mast cell

degranulation occur with an increase in viral illnesses, allergy, and

malignancy, along with failure of other zinc dependent functions such as growth.

 

Still, no specific zinc linkage has been established that actually explains the

occurrence of malignant transformations. However, it would be of interest to

conduct studies using low level radiation on normal blast cells in vitro

deprived of zinc transferrin compared with cells replete with zinc transferrin.

Such studies have not been done although a similar study with no direct

attention to zinc bioavailability using carefully nourished mouse fibroblasts

found an extraordinarily higher cell transformation rate than had ever been

previously expected from low level dental and medical diagnostic X-rays.

 

One out of every 10,000 cells was malignantly transformed (Ref. 41). It is

important to know if any washing was done with a metal chelator such as EDTA. If

so, the zinc in the genetic material could have been so depleted so as to allow

the cells to be defenseless against cellular transformation induced by low level

radiation or other ionizing sources. This important experiment should be

repeated paying careful attention to the role of zinc in the genetics of the

cells.

 

 

 

--

 

VIII. THE TEXAS COLD CURE EXPERIMENT (PRE CLINICAL TRIAL ANECDOTAL EVIDENCE)

 

The Texas Cold Cure Experiment was an informal field study conducted during

1979, 1980 and 1981. It involved the use of zinc gluconate in the experimental

treatment of common colds, allergic rhinitis, bronchial asthma, croup, food

allergy and gastrointestinal allergy in field environments.

 

The experiments were primarily conducted to ascertain if the role of zinc in

normal health could suggest whether or not abnormal zinc metabolism could cause

symptoms noted in pre leukemia and active leukemia.

 

In other words, could these symptoms be reversed by additional zinc, and if so

what significance do the findings have for the treatment of leukemia, and can

additional zinc benefit the person with leukemia. Although the answers still

need definition, a trend is clear.

All experiments were uncontrolled but used the individual's previous health

history and results of repeated trials with and without zinc to reduce the

possibility of faulty observations.

 

The theoretical basis for the experiment is found in the preceding parts of this

review. Briefly stated, zinc can prevent the abnormal release of histamine and

other mast cell constituents, can retard suppressor cell function where

excessive, can stimulate effector T-cell function and effector T-cell mitosis,

and can have direct and anti-viral functions.

 

Zinc gluconate was used in preference to zinc sulfate since it was observed to

cause less or no gastric disturbance in the dosages used.

 

Zinc gluconate tablets with no sweeteners were also dissolved in the mouth as

throat lozenges.

 

Since very high levels of long term zinc administration can interfere with

absorption of copper, manganese, selenium, iron and other minerals, and also

necessitates higher Vitamin A intake, recommendations for a mild supplementation

of these nutrients were also made.

 

Best results occurred with 150 mg zinc in the morning and 150 mg zinc at bed

time.

_

Moderator's Note: Copper competes with Zinc so it is important to ensure that

your copper intake is minimal for maximum zinc absorption. Copper may be taken

in from your drinking water as well, from any existing copper pipes.

________________

 

JoAnn Guest

mrsjoguest

DietaryTipsForHBP

http://www.geocities.com/mrsjoguest

 

 

 

 

 

 

 

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