Zinc in Leukemia

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Zinc in Leukemia JoAnn Guest Apr 28, 2005 21:49 PDT

 

 

George Eby

 

Introduction. RATIONALE FOR STUDY AND SUMMARY OF FINDINGS

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In a case of Acute Lymphocytic Leukemia (ALL)in a 3-year-old white

female treated with CCG protocol 161, regimen 2 a bone marrow remission

from 95+% blast cells to an observed zero blast cell count (not M-1 but

M-0) occurred within 14 days of treatment.

 

During this same period adult therapeutic doses of all known vitamins

(except folic acid) and all minerals and trace minerals were also given.

In addition to the reduction of blast cells to an observed count of

zero, red blood cell production and other hemopoietic functions returned

to a modified normal condition at a clinically remarkable rate. No

adverse effects of the chemotherapy were observed. Since most remissions

after 30 days of treatment still show 3-5% blasts in the bone marrow,

the question " Had there been an unknown but positive interaction between

one or more of the supplemental nutrients and the chemotherapy? " was

asked by the clinicians and parents. Research was initiated to ascertain

if a nutrient deficiency could cause symptoms found in pre-leukemia and

leukemia; and if such nutrient exists, would a positive interaction

occur if it were administered as an adjunct to chemotherapy. If a

nutrient could be shown to accelerate and strengthen the function of

chemotherapy or the immune function, then it could be expected that the

relapse rate could be lessened since the relapse rate to both the rate

at which a remission is obtained and the thoroughness of the elimination

of leukemic blasts.

 

Based upon a review of the available literature, only zinc deficiency or

zinc metabolism errors could theoretically cause all of the pre-leukemic

conditions of allergy, loss of viral and tumoral immunity, asparagine

production, growth suppression and other commonly observed pre-leukemic

conditions. 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

 

Pre-Acute Lymphocytic Leukemia in the child is often, but not always,

marked by: (1) severe atopic-like allergic reactions, (2) major and/or

frequent upper respiratory viral infections and fevers, (3) taste and

appetite suppression, (4) growth suppression, (5) lethargy and

depression, (6) diarrhea, and (7) offensive body odor. These symptoms

are more often noted by the family and pediatrician than by the

oncologist. They have not previously been associated with leukemia in

terms of their having a common nutritional origin.

 

The occurrence of one or more of these symptoms is frequent enough in

the year preceding the onset of ALL to suggest that there may be a

nutritional linkage, or common denominator, between them individually

and between them and leukemia. Obviously, they are not normally

predictive of leukemia. In fact, many are typical of what has come to be

considered as normal childhood problems that eventually go away with or

without treatment, although nutritional deficits could still be causal.

 

Since no other etiology of leukemia exists, this backward-looking

approach seemed to offer at least a chance to develop an hypothesis

concerning 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.

 

If leukemia is to be prevented or its incidence lessened, a better

understanding of the role of individual nutrients in the etiology of

pre-leukemia symptoms appeared to be necessary. If a role for a single

nutrient could be found for each of the symptoms of pre-leukemia,

leukemic cell involvement, and recovery, a major break-through in the

prevention of childhood leukemia via nutritional means could eventually

be forthcoming.

 

 

 

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II. ZINC DEPLETION, THE COMMON DENOMINATOR IN THE PRE-LEUKEMIC CONDITION

 

 

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 following is a review of the role of zinc in the management and

cause of the pre-leukemic symptoms. It is from the zinc perspective that

many previously unrelated symptoms seem to share a common genesis. 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.

 

ALLERGY

 

Mast cells and basophils are commonly known to be the mediators of Type

I allergy. Hayfever, food allergy, asthma, croup, gastrointestinal

allergy, and anaphylaxis are manifestations of Type I allergy. Allergic

reactions result from the release of histamine, heparin, slow-reacting

substance of anaphylaxis (SRS-A) and kinins from the cell's granules.

The release, generally, is caused by a reaction of antigen with mast

cells or basophils coated with IgE antibody. This reaction causes a

degranulation of the cell's contents and active transport of the cell's

contents through the cytoplasmic membrane of the cell. (Ref. 1, p. 329).

 

 

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 leukemic children are the cause of the severe allergy-like

symptoms that precede leukemia. That they occur in children 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.

 

In addition to zinc stimulation of effector T-cells, lithium is now

being used to significantly minimize the leukocyte immunosuppression

caused by some cancer chemotherapy drugs with a ten-fold reduction in

infection, and even greater reduction in mortality (Ref. 24). Mixtures

of lithium, zinc and calcium have been shown to stimulate lymphocyte

transformation to levels observed for lectin stimulation (Ref. 9).

Lithium appears useful in treating children with certain kinds of

chronic neutropenia (Ref. 69).

 

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 acute lymphocytic 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.

 

No significant toxicity has been demonstrated in humans at the dosages

used in these experiments. Major toxicity symptoms can occur at doses in

excess of 15 grams per day. Zinc is nonaccumulative. Zinc has been

observed to be lethal at a single dose of 45 grams. Symptoms of long

term zinc toxicity in humans include drowsiness, lethargy, increased

serum lipase and amylase levels, vomiting, dehydration, electrolyte

imbalance, abdominal pain, nausea, dizziness, muscular incoordination,

and acute renal failure (Ref. 6, p. 17) and probably necrotizing

pancreatitis.

 

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.

 

Pregnant women and those who were medically immunosuppressed to prevent

host-versus-grant disease were considered to have purposefully abnormal

zinc metabolism and were not allowed to participate in the experiments.

Theoretically zinc at these dosages could reinstate their immunity with

the potential of abortion or host-versus-graft disease.

 

The lack of severe toxicity of zinc gluconate specifically has been

observed in a case where a young woman ingested between 440 and 5700 mg

zinc every day for 4 months. The most evident clinical changes were

severe anemia, neutropenia, a ten-fold zinc serum level and a one-tenth

copper serum level. Complete recovery occurred with withdrawal of zinc

and supplementation of 2 mg copper/daily (Ref. 82). The woman ingested

the zinc in split doses each two hours.

 

ALLERGY

 

Theoretically zinc should prevent the release of histamine from mast

cells and basophils. The amount needed at the beginning of the

experiment was unknown. After repeated early trials, it was generally

found that 1/2 - 2 mg zinc per pound of body weight in any age group was

adequate for the improved management of any allergic symptom. The time

for management of symptoms to occur varied from minutes for post nasal

drainage to months for food allergies. Finding a correct dosage was

slightly individualistic, and the response time was quite

individualistic.

 

In general, symptoms of nasal rhinitis, including fatigue, irritability,

depression, blocked Eustachian tubes, inflammation of tonsils, excessive

nasal congestion, nasal drainage, post nasal drainage, coughing, sleep

disturbances, headaches and sore throats could be eliminated or greatly

relieved so long as the zinc therapy was maintained in most of the

experimental trials.

 

It was found that the dose-response was non-linear with limited or no

benefit at zinc intake just under the effective dose. It may be that

this effect results from the competition of the zinc transport ligand

and mucosal metallothionein synthesis in the intestinal lumen. Such a

mechanism could be easily overcome at high levels of zinc intake with

picolinic acid and in these cases metallothionein synthesis may be

induced in the liver where excess zinc is either bound there or

alternatively by individual cells (Ref. 15, p. 1262). The following are

several examples.

 

One adult female subject had such a chronic and severe atopic nasal

rhinitis with post nasal drainage that she could not sleep in the normal

reclining position. Under her doctor's orders she sat upright strapped

into a chair to sleep in order to prevent drowning from post nasal

drainage. No antihistamine was effective. No immunotherapy was

effective. The condition lasted 7 years. Upon supplementing her diet

with zinc gluconate at 1 mg per pound of body weight, post nasal

drainage cleared, her nasal passages returned to normal, and all other

symptoms were eliminated. She felt much better and gained weight with an

improvement in personal appearance and disposition. She now sleeps in

the normal reclining position. Her nasal problem returns if zinc (zinc

picolinate) is not supplemented every 12 hours. No adverse reactions

occurred.

 

One adult male subject has 29 years of severe nasal allergy and 15 years

of food allergies. Antihistamines were ineffective. Desensitization was

attempted 3 times with no permanent improvement. Zinc therapy resulted

in immediate reduction in some symptoms. Nasal and food allergies became

less pronounced with time. After three months nasal passages were

completely normal and food allergies were absent. After three months,

challenges with foods that previously produced severe headaches failed

to produce any allergic response. Nasal allergy symptoms returned in

18-24 hours without zinc therapy. The individual weighed 160 pounds.

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

bed time. See Chandra for toxicity to T-cell system in well subjects,

not ill subjects. Chandra found in healthy medical students that double

maximum high normal serum levels (300 mmg/DL) 300 mg dietary zinc a day

first increased (doubled) T-cell function, but after 30 days, blood

serum level gradually rose over the normal upper limit of zinc (150 mmg

zinc/dl) and T-cell function fell to 20% of normal.

_________________

 

 

JoAnn Guest

mrsjo-

DietaryTi-

www.geocities.com/mrsjoguest/Genes

 

 

 

 

 

AIM Barleygreen

" Wisdom of the Past, Food of the Future "

 

http://www.geocities.com/mrsjoguest/Diets.html

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[Guest guest]

Can you recommend anything natural for 'hand tremors'?

 

Thank you JoAnn

--- JoAnn Guest <angelprincessjo wrote:

 

> Zinc in Leukemia JoAnn Guest Apr 28, 2005 21:49

> PDT

>

>

> George Eby

>

> Introduction. RATIONALE FOR STUDY AND SUMMARY OF

> FINDINGS

> http://coldcure.com/html/dep.html

>

>

> In a case of Acute Lymphocytic Leukemia (ALL)in a

> 3-year-old white

> female treated with CCG protocol 161, regimen 2 a

> bone marrow remission

> from 95+% blast cells to an observed zero blast cell

> count (not M-1 but

> M-0) occurred within 14 days of treatment.

>

> During this same period adult therapeutic doses of

> all known vitamins

> (except folic acid) and all minerals and trace

> minerals were also given.

> In addition to the reduction of blast cells to an

> observed count of

> zero, red blood cell production and other

> hemopoietic functions returned

> to a modified normal condition at a clinically

> remarkable rate. No

> adverse effects of the chemotherapy were observed.

> Since most remissions

> after 30 days of treatment still show 3-5% blasts in

> the bone marrow,

> the question " Had there been an unknown but positive

> interaction between

> one or more of the supplemental nutrients and the

> chemotherapy? " was

> asked by the clinicians and parents. Research was

> initiated to ascertain

> if a nutrient deficiency could cause symptoms found

> in pre-leukemia and

> leukemia; and if such nutrient exists, would a

> positive interaction

> occur if it were administered as an adjunct to

> chemotherapy. If a

> nutrient could be shown to accelerate and strengthen

> the function of

> chemotherapy or the immune function, then it could

> be expected that the

> relapse rate could be lessened since the relapse

> rate to both the rate

> at which a remission is obtained and the

> thoroughness of the elimination

> of leukemic blasts.

>

> Based upon a review of the available literature,

> only zinc deficiency or

> zinc metabolism errors could theoretically cause all

> of the pre-leukemic

> conditions of allergy, loss of viral and tumoral

> immunity, asparagine

> production, growth suppression and other commonly

> observed pre-leukemic

> conditions. 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.

>

>

>

>

--

>

>

>

> I. A SEARCH FOR THE ETIOLOGY OF LEUKEMIA

>

> Pre-Acute Lymphocytic Leukemia in the child is

> often, but not always,

> marked by: (1) severe atopic-like allergic

> reactions, (2) major and/or

> frequent upper respiratory viral infections and

> fevers, (3) taste and

> appetite suppression, (4) growth suppression, (5)

> lethargy and

> depression, (6) diarrhea, and (7) offensive body

> odor. These symptoms

> are more often noted by the family and pediatrician

> than by the

> oncologist. They have not previously been associated

> with leukemia in

> terms of their having a common nutritional origin.

>

> The occurrence of one or more of these symptoms is

> frequent enough in

> the year preceding the onset of ALL to suggest that

> there may be a

> nutritional linkage, or common denominator, between

> them individually

> and between them and leukemia. Obviously, they are

> not normally

> predictive of leukemia. In fact, many are typical of

> what has come to be

> considered as normal childhood problems that

> eventually go away with or

> without treatment, although nutritional deficits

> could still be causal.

>

> Since no other etiology of leukemia exists, this

> backward-looking

> approach seemed to offer at least a chance to

> develop an hypothesis

> concerning 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.

>

> If leukemia is to be prevented or its incidence

> lessened, a better

> understanding of the role of individual nutrients in

> the etiology of

> pre-leukemia symptoms appeared to be necessary. If a

> role for a single

> nutrient could be found for each of the symptoms of

> pre-leukemia,

> leukemic cell involvement, and recovery, a major

> break-through in the

> prevention of childhood leukemia via nutritional

> means could eventually

> be forthcoming.

>

>

>

>

--

>

>

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