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.

 

 

 

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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.

 

 

 

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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.

 

 

 

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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?

 

 

 

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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.