Malcolm Adams Traill

Mal's Musings

Malcolm A Traill

IN  THE  PUBLIC  INTEREST
Updated 18/1/2009

 

 

MULTIPLE MYELOMA AND LITHIUM

 

A CAUSE FOR HOPE ?

 

 

Following-on from the placement of the Chapters on Lithium and its effects on cancers, (particularly Prostate Cancer), on the website, a man with multiple myeloma sought to treat his condition with Lithium, using the same general protocol. This Chapter presents a summary of Multiple myeloma, the chemical treatment options and early experiences with Lithium presented as a �sneak preview :�

 

The malignancy, Multiple myeloma : Multiple myeloma is a malignancy that features an uncontrolled  proliferation of cells of the plasma cell series. These cells make most antibodies in the blood, and each patient has an oversupply of one (occasionally two) unique antibody (monoclonal; paraprotein). Unfortunately, this swamps and competes with the good, general purpose antibodies (polyclonal) represented by the general term �gamma globulin,� so that there is an increased risk of infection. The malignant plasma cells are chiefly found in nests in the bone marrow, where the numbers slowly increase, compromising the blood-forming elements (red cells, white cells and platelets) and cause bone dissolution, which can result in the serum Calcium rising. The nests tend to create �holes� in the bony structures, giving a characteristic appearance of �punched-out� bony lesions on X-ray.

The manufacture of the monoclonal antibody by the malignant plasma cells is disorganized, so that smaller precursor fragments can be found in the serum and urine (Bence Jones protein; light chains). This, and/or a rising serum Calcium can give rise to renal impairment that can lead to renal failure; so attention to renal function is very important.   

 

The Chemical Treatment options of Multiple Myeloma[1] :

Excluding plasmapheresis, dialysis and high dose therapy with autologous stem cell transplantation from consideration here, the traditional treatments have been with corticosteroids (Cortisone, Prednisolone, Dexamethasone etc.), the anti-neoplastic, alkylating and nitrogen mustard-related drug, Melphalan. Others include Cyclophosphamide, Doxorubicin (�Adriamycin�), Vincristine and, more recently, Thalidomide and Bortezomib. Whilst the traditional objective response rate is quoted at only 50-60%, there are benefits claimed, with the median survival following chemotherapy with the objective response some 48 month, overall ~3� year[2].

Recently, there has appeared some interest in the potential use of Lithium[3]. Using Lithium applied by oral gavage to mice once a day and an experimental mouse model for Multiple myeloma, the researchers noted benefits, provided the malignant cells were within the bone marrow; those outside seemed to be stimulated by the Lithium. The serum levels (from an earlier study)[4] had been measured some 2 h after the gavage dose and the mean level was 0.413 � 0.05 mmol/L. This level was unlikely to be the peak � the peak, probably being ~ +10% above the measured levels[5], ≈ 0.45 mmol/L, rather a low dose, based upon human values. The technicalities of the rationale behind the Lithium use and findings need not be presented here, other than emphasizing that the Lithium dosing was a daily routine, (as opposed to an alternate day regime), which seems to make all the difference ! (There are, of course, the obvious and uncertain differences between mice and men, and between the natural human multiple myeloma and the injected cell strain used in the mice.)

Whilst there may be a reduced incidence of malignancies in those psychiatric patients receiving Lithium over the last 50 or so years[6], we may assume that there will have been some patients with multiple myeloma who received Lithium. There does not appear to be any indication that lithium had any observable effect, good or bad, upon the disease. If any patient with Multiple myeloma has received the Lithium as a specific treatment for the condition, that does not seem to be readily available yet.

The man to be reported here is probably the first case of Multiple myeloma to have received the Lithium in an alternate day bolus regime, if not the first in the world to receive Lithium specifically to treat his Multiple myeloma (see elsewhere on this website).

The documentation is sketchy and incomplete �and concludes a bit like JS Bach�s Die Kunst der Fuge ! Perhaps there may be more to come � perhaps not. Given the uniqueness of the opportunity, what has been gleaned to date will be examined in detail, in order to extract the maximum of useful information for the assistance of other therapists, researchers and patients.

 

The Subject: The man (MuM) was 68 years old, slim (height 173 cm) and a heavy smoker, claiming some 60 cigarettes per day. He noticed a �stiff neck� with pains approaching �agony� in about June. He had noted loss of weight. After basic investigations for these, he acquired a diagnosis of multiple myeloma based upon a bone marrow examination, with immature plasma cells (a poor prognosis given) Computerized Tomography (CT) of the total skeleton, revealing multiple small lytic lesions, a paraprotein peak in his slow gamma globulin region on electrophoresis, characterized as monoclonal IgGκ, quantified at 40 g/L. The other relevant laboratory results are presented in Table 1. A whole body 99mTc-MIBI (�Sestamibi�) scan did not demonstrate any focal lesion (indicating that the myeloma foci were of small diameter, and there are no appreciable extra-marrow masses)

MuM attended an Oncologist who, though he prescribed chemotherapy, was not enthusiastic about it (according to MuM) ! The patient, after inquiry, concurred, and did not take any of the prescribed medication. (He was also influenced by a near neighbour who had had multiple myeloma and chemotherapy, with appreciable unpleasant side effects).

During October, he chose to attend the Radiowave Therapy Clinic[7] in Western Australia (UHF 434 MHz)[8], which provided symptomatic relief within three days.

After some limited base-line tests (restricted because of organizational problems, and revealing mildly reduced renal function since the UHF treatment), he commenced Lithium Rx therapy (November 25th), using the protocol set out in other Chapters[9] (500 mg of Lithium Carbonate �Lithicarb,� two bolus doses 6 h apart.)  His weight then was 58 kg. Shortly after having 1� Lithium Rx cycles, he was found to have a large intra-abdominal aortic aneurysm. This disturbing finding diverted attention from the Lithium Rx for some days; he recommenced it again in early December. A CT scan report observed that the aneurysm started below the renal arteries, so that the declining renal function was probably related to nephrosclerosis with multiple myeloma paraprotein and protein fragments.

He did not organize a Lithium serum level test until about 3 weeks of Lithium Rx. When it was measured, some 28 h after a missed Lithium Rx pair, it was 0.5 mmol/L. Based upon the working hypothesis (unproved) that the serum Lithium level should fall to ineffective levels between Lithium Rx cycles, this value was deemed too high, so the comment on December 18th was that the doses would best be reduced to 375 mg x 2 per treatment day (1� Lithicarb tablets, repeated after 6 h). He noted no symptoms referable to Lithium intoxication.

 

Early Investigations: Whilst the diagnosis had been made and would not seem to be in any doubt, sadly, certain baseline tests were omitted, such as the Serum Calcium, inorganic Phosphate and Corrected Calcium, and Urate. The absence of these makes later assessments difficult. Overall, some comments and assumptions may be made about MuM�s renal function, with main points shown in Table 1 :

 

Multiple Myeloma and Renal Function[10] � particulars regarding MuM

 

TABLE 1

 

 

                             

 Feature                                         Patient MuM                              Conclusion

 

Serum Creatinine

Initially 99 μmol/L

Later 112 μmol/L

(1 mg/dL = 88.4μmol/L)

No appreciable renal failure at presentation; MuM�s monoclonal κ light chains are not particularly nephrotoxic

Urine, Bence Jones protein 

κ light chains

Nephrotic syndrome unlikely � watch for light chain deposition disease and Fanconi syndrome

Serum albumin electrolytes and urate

~Normal.

No clear indication of nephrotic syndrome or Fanconi syndrome 

Serum Calcium & Inorganic phosphorus; ALP

~Normal initially

No appreciable bone loss or osteoporosis

 

Treatments

MuM received two treatments relatively close together � the Lithium Rx being commenced at about 4� week following the 434MHz UHF treatment � at a time when the latter may still be expected to be having some effect (the usual protocol was to review such patients at 6 week after the UHF treatment). So, both treatments must be considered:

 

Tumour Markers and their changes

Here, there is some point in discussing Tumour Markers. These are usually glycoproteins in the blood, produced either by the tumour in greater amounts than from normal tissues (eg carcino-embryonic antigen), or are sufficiently specific to provide a measure that likely reflects tumour bulk (eg prostate-specific antigen). To be in common use, the methods for determining them need to be generally commercially available to laboratories.

In an undisturbed state, the tumour marker provides some measure of tumour bulk and, accordingly, if measured sequentially, gives an indication of the tumour growth rate, from which a doubling time may be estimated when sequential values are available.

Most glycoproteins to reach the blood have their protein manufactured initially in the cells� cytoplasm by ribosomes. The product is drained by the fine channels (endoplasmic reticulum) to the Golgi[11] apparatus, which is essentially a sump. It is an irregular structure of clefts, roughly a shell around the centrosome, which is located near the cell nucleus. When the protein precursor reaches the Golgi, it has sugar groups attached and then released into the circulation as a glycoprotein.   

In the case of MuM, his tumour marker is the effectively pure monoclonal gamma globulin (paraprotein) produced by the malignant plasma cells, and using the same general manufacturing plan as outlined above.

When tumour cells are disturbed, as by some anti-cancer treatment, and they are damaged, they may break down and release the cell contents. This affects the interpretation of the changes in tumour markers. The types of patterns are illustrated in Figure 1.

 

FIGURE 1

 

                                                     

Figure 1: These graphs are idealized representations of actual or hypothesized tumour marker responses with time, following three forms of treatment administered after a monitoring interval (Before Rx; Black). Note that the vertical axis is logarithmic. Three treatment types are considered :  (a) Chemotherapy (square; red) , which produces a fairly rapid rise and fall of the tumour marker;  (b) 434 MHz UHF (triangle;green). This produced an initial fall in the tumour marker, earlier attributed to disruption of the Golgi when the cells had their divisions blocked because of the heat damage to the centrioles (centrosome).  There was a later rise as the tumour cells slowly disintegrated; (c) Lithium Rx (star; blue), where there is hypothesized to be a response similar to that for 434 MHz UHF, again possibly involving the Golgi.  These curves are hypothetical and are simply to assist understanding. There may be considerable individual variation in the patterns actually obtained in practice.

 

Tumour lysis.  Related to the tumour sensitivity and the specific form of treatment coupled with the tumour bulk, a considerable quantity of breakdown products may be released into the circulation. Notable is uric acid/urate which, being relatively insoluble, can precipitate in the kidneys and, if bad enough, lead to renal failure. Other chemicals are also released; both serum potassium (early) and inorganic phosphate rise and, since the phosphate normally has an inverse relationship with calcium, there results a fall in the serum calcium (see later).

If these changes are sufficiently prominent to cause symptoms or concern, the events are described as the Tumour Lysis Syndrome[12]. The high fluid intake recommended for those patients at risk is to maintain a high fluid input to wash the urate out through the kidneys and stabilize the electrolytes.

 

The effects of the 434 MHz UHF treatment. Despite the Radiowave Therapy Clinic�s claim to be researching the effects of the UHF treatment, MuM could produce no results derived from, or soon after his stay in Western Australia. The first assessment test following the UHF were taken at about 4� week from the completion of the UHF course, and many of the tests considered desirable then were not done ! Examination of the paraprotein levels and the calculations there-from, whilst difficult and imperfect, indicate that the doubling time may be about 4.5 year. The more relevant results are set out in the Table 2.

 

TABLE 2

 

Diagnosis   8 week                    19 week (from diagnosis)

Baseline          Before UHF    4� week after UHF

                                                           Reference Range

Haemoglobin g/L                      120                  111                  119     130-180

Neutrophils x109/L                   5.3                   4.7                   5.6       2.0-8.0

Lymphocytes x109/L                 2.2                   2.0                   2.9       1.0-4.0

Monocytes x109/L                    0.4                   0.4                   0.6       <1.0                   

Platelets x109/L                        625                  652                  577      150-450

 

Potassium mmol/L                    4.4                   4.6                   4.2      3.7-5.3

Creatinine μmol/L                     99                    98                    112     55-110   

Urate mmol/L                           ND                           ND                    0.37     0.18-0.47

Calcium(corrected+) mmol/L     ND                           ND                    2.43     2.10-2.60

Inorganic Phosphate mmol/L     ND                           ND                    1.42     0.75-1.45

Albumin g/L                              39                    38                    40        35-50

Globulin g/L*                            62                    63                    70        NQ

Paraprotein g/L (IgG)                 40                    41@                 48@      undetectable      

ALP U/L                                  117                  ND                    116      40-130

�Anion gap�# mmol/L                2.4                   -1.4                  2.2      10-20[13]

 

ND = Not determined; NQ= Not quoted, being total protein (60-81 g/L) � Albumin ≈ 20-46 g/L

+Corrected Calcium ≈ Calcium x 40/Albumin

*Calculated; total protein � albumin

#Calculated; Sodium + Potassium � Chloride � Bicarbonate; a crude estimate of charged peptides

@Calculated: Total protein � albumin � polyclonal gamma globulin (taken from earlier and later tests)

The changes of note are :

       The haemoglobin level rose from 111 g/L to 119 g/L����.  good

       The neutrophil count rose from 4.7 to 5.6 cells x109/L���..   good

       The lymphocyte count rose from 2.0 to 2.9 cells x109/L   ���good

       The (estimated) paraprotein level rose from ~41 g/L to ~48 g/L

       The albumin level rose from 38 g/L to 40 g/L

       The anion gap rose from -1.4 mmol/L to 2.2 mmol/L

       The creatinine rose from 98 μmol/L to 112 μmol/L

Whilst some of the changes can be classified as clearly good, others need analysis :

o      The rise (5%) of the serum albumin may be due to a mild dehydration, meaning that the haemoglobin and paraprotein levels may be similarly affected on that day

o      The paraprotein rise (corrected for ? dehydration) of ~5 g/L in 77 day is not consistent with a doubling time of ~4.5 year. The two likely explanations for the rise would be tumour breakdown, with the release of the paraprotein, or a discrepant result from the laboratory. The subsequent fall back to 41 g/L (see Table 3) in 9 day needs analysis :

Assuming the total globulin (paraprotein + polyclonal globulin) is as reported, when the result is plotted with the values 9 day later, derives an half-life of ~7� week. The half-life, based upon values 5% lower is ~ > 12 week. Analyses to establish expected γ-globulin half-lives are rather elusive in the literature. The best reference found to date provides work involving children with a mean age of 27 months[14].  In that study, the children had Kawasaki disease and had intravenous infusions of �S-sulphonated intact gammaglobulin.� The mean post infusion γ-globulin level was ~ x 3 times the pre-infusion level, which is somewhat similar to the state for MuM, whose total γ-globulin was ~ x 3 the polyclonal γ-globulin level. (However, much of MuM�s γ-globulin was being replaced by the disease process.) The γ-globulin fall in the children was close to linear and, on that basis, showed an half-life of ~2.6 week.  The major differences in the children and MuM are the age gap and the Kawasaki disease state. Another reference, without source or kinetic details, gave an half-life of ~23 day[15].

MuM�s paraprotein half-lives based on the two points, and found over the 9 relevant day interval are well above those found in the literature. This means that either the paraprotein level had fallen to ~pre-treatment levels before the 9 day review, or that the real fall was more but masked because the levels were being maintained by tumour-cell breakdown over a new background level, consistent with a late effect from the 434 MHz UHF treatment. The rise in the anion gap may indicate a reduction of smaller, charged oligo-peptides in the serum (light chains). They may be lost relatively rapidly. The rise continued into the Lithium Rx interval.

o      The mild rise in the serum creatinine is of more concern. The likely causes for this could be some renal damage from a surge in light chains reaching the kidneys, or some effect of the 434 MHz UHF protocol on renal function. Whilst the �GBA; glucose blocking agent� used by the current practitioners in not known for certain, it is probably a mixture of oxidized glutathione and S-methyl-L-cysteine sulphoxide; the former explanation is currently being favoured, or a combination of the two. (Subsequently, there seemed little evidence of improvement � see Table 3.)

In conclusion, regarding the 434 MHz UHF treatment, there are features that can be regarded as favourable and encouraging, but the evidence cannot be considered to be at the required level for any proof of efficacy. The change in the serum creatinine level may need ongoing consideration.

 

The effects of the Lithium treatment

 

Noteworthy results are set out in Table 3, (which includes the last column of Table 2).

 

TABLE 3

 

Pre-Lithium    From start       From start

Baseline          +9 day             +21 day

                                                           Reference Range

Haemoglobin g/L                      119                  ND                    118      130-180

Neutrophils x109/L                 5.6                   ND                    7.3       2.0-8.0

Lymphocytes x109/L                 2.9                   ND                    2.5       1.0-4.0

Monocytes x109/L                    0.6                   ND                    0.6       <1.0        

Platelets x109/L                        577                  ND                    609      150-450

 

Potassium mmol/L                    4.2                   4.9                   5.3       3.7-5.3

Creatinine μmol/L                     112                  116                  117     55-110

Urate mmol/L                           0.37                 0.4                   0.39     0.18-0.47

Calcium (corrected) mmol/L     2.43                 ND                    2.77    2.1-2.6

Inorganic Phosphate mmol/L     1.42                 ND                   1.63     0.75-1.45

Albumin g/L                              40                    38                    38        35-50

Globulin g/L*                            70                    64                    73        NQ (see Table 2)

Paraprotein g/L (IgG)               48@                  41                   48        undetectable

ALP U/L                                  103                  126                  107      40-130

LD U/L                                    173                  188                  175      50-280

�Anion gap�#  mmol/L   2.2                   5.9                   3.3       10-20

Note: the Pre-Lithium column is the same as the �After UHF� column of Table 2. For clarity, this format is used to try to present separately, the two forms of treatment received.

The other notes/annotations are as for Table 2.

Those items highlighted in dark red, are typically involved following tumour breakdown; those above the upper limit of the reference range are underlined

 

Results of particular note are :

       The neutrophil count rose from 5.6 to 7.3 cells x109/L

       The lymphocyte count fell mildly from 2.9 cells x109/L to 2.5 cells x109/L. such a mild fall in the circumstances would not normally attract much attention, except that for both previous patients PC (prostate cancer) & LC (lung cancer), the lymphocyte counts rose initially. In the case of LC, where tumour size reduction occurred probably by about day 18 (CEA change), the graph of her lymphocytes showed a decline evident at about day 44, there being no results between day 20 and day 44. The decline in her count may have been due to consumption/toxicity.

       The serum potassium level rose steadily. This slow response is not typical for the tumour lysis syndrome, where potassium is an early riser. It may represent a progressive tumour breakdown, coupled with a mild reduction in renal function.

       The serum urate shows a rise in the first days, with a plateau. This is not a big rise, but it could be consistent with a progressive tumour breakdown.

       The serum Calcium has risen from 2.43 mmol/L to 2.77 mmol/L, the latter above the upper limit for the quoted reference range. This runs contrary to the pattern reported in the tumour lysis syndrome, where inorganic phosphate is released and, as a consequence, brings the Calcium down. The rise could for-shadow malignant hypercalcaemia, a condition that can be associated with multiple myeloma. In this connection, two patients with lymphoma who received the 434 MHz UHF treatment developed malignant hypercalcaemia in the second week of the treatment course They both required intravenous Pamidronate. The rise here may have a similar biochemistry (see later).

       The serum inorganic phosphate rose from 1.42 mmol/L to 1.63 mmol/L, the latter being above the upper limit of the quoted reference range. This is consistent with a mild form of the tumour lysis syndrome. As noted above, one would expect the phosphate to pull the Calcium down, but it has not done so. We are left to consider two processes operating � (a) the tumour breakdown of the tumour lysis syndrome type, and also (b) a process opposing this with regard to the serum Calcium � the latter being released from the intracellular stores (mainly in the endoplasmic reticulum, of which plasma cells have a lot) and/or by some humoral effect(s) upon bone metabolism. The implication is that the observed rise in the serum Calcium is actually less than it would have been had the phosphate level been normal.

        There was a ~7 g/L rise in the paraprotein level. We cannot be certain of the status of the level of 41 g/L; it may have been falling at that stage following the 434 MHz UHF treatment (see earlier), in which case, the rise could be appreciably more and �mopping up� the cells that the 434 MHz UHF treatment did not damage. (When the results for the paraprotein levels were examined, the possibility that the 21 day result could have involved a laboratory error was considered. Accordingly, the laboratory was contacted, and the specimen re-run on the 3 machines that could have been involved. The total protein, being the key result from which the paraprotein was calculated, produced, on retesting, results of 109,109 & 108 g/L, compared with 111 g/L originally. Whilst the difference could come within the expected testing variations, there was also the possibility that cryoglobulins had precipitated-out during the refrigerated storage. Accordingly, the original and reported values were retained.)

       The ALP and LD show very minor changes which, however, would be consistent with some cellular perturbations at 9 day.

       The anion gap may indicate an initial decrease in light chains, later reflecting an increase that could be consistent with tumour breakdown.

 

Comments for MuM included :

       That the rises in the paraprotein levels were inconsistent with natural, or hastened progression of his Multiple myeloma and

       They were consistent with tumour cell breakdown (desirable).

       He would need to maintain high fluid intake

       The serum Lithium and Calcium levels needed to be monitored closely.

There has been no further communication.

 

So, folks, now for the conclusions overall.

Adopting thenull hypothesis approach, by which there would be the claim that both the 434 MHz UHF and, later, the Lithium Rx had no appreciable impact upon MuM�s condition (ie were not appreciably different from placebo) :

       Neither treatment has had time to demonstrate any long-term effect

       Neither treatment has resulted in (or was associated with) a measurable drop in the pre-treatment paraprotein level as yet (see above)

       Short-term, the acute effects that have been noted for both treatments are encouraging and could be considered consistent with effects greater than those that would be dismissed as due to placebo (434 MHz UHF), and with reasonably convincing evidence that there have been identifiable tumour cell responses � something had been happening (Lithium Rx), which would seem, overall, likely to be desirable.

       On the available data, the impression is that the Lithium Rx is better, cheaper and probably safer than the 434 MHz UHF.

       The assessment of both treatments is hampered to an appreciable degree by the paucity of laboratory investigations and follow-up.

       Further use of this Lithium Rx is warranted, but there needs to be close monitoring of the serum Calcium (in addition to the Lithium and creatinine).

       There is no clear evidence that the Lithium Rx had any significantly harmful effect (relative to other treatments).

 

So, now for some thoughts on the mode of action of the Lithium Rx.

Elsewhere on the website, there was an analysis of Lithium�s actions as an initiator of hyperacute or acute biochemical processes within cells (as opposed to the subacute � chronic responses involved in psychiatry). The appreciably differing effects of daily administration versus alternate day dosing have remained an enigma.

However, a recent publication may provide important new insight[16]. In this, a new enzyme found in the Golgi and belonging to a known enzyme family, has been described and studied. The enzyme, Golgi-resident 3�-Phosphoadenosine 5�-phosphate 3�-Phosphatase is abbreviated gPAPP, and is considered to be the enzyme that is most sensitive to Lithium inhibition found to date. It is involved in the formation, within the Golgi, of the Glycosaminoglycans, such as Chondroitin sulphate (sulfate) and the Heparan sulphates (which are similar to Heparin, but associated more with the cell plasma membranes). Homozygous mutations of the gPAPP genes in mice result in a lethal phenotype which displays, as one of the abnormalities found before birth, a lung condition characterized by a proliferation of alveolar lining cells, showing no clear organization, but cell rounding, poor cell adhesion, occasional wisps of free cytoplasm and occasional pyknotic nuclei � appearances that are faintly reminiscent of the changes seen in the prostate cancer cells of patient PC[17]. Of course, there will be the sceptics who note that the comparison is between the foetal lung of a mouse and the malignant prostate of an aging human, but both do have in common the characteristic immaturity (given that cancers are considered to show regression to more immature behaviour). There may also be some similar features in the quite artificial system involving EXT1 and the disruption of Heparan formation upstream of gPAPP, as shown in embryoid bodies of other workers[18], and which showed that the Heparans were essential as cofactors in the maintenance of the stem cell pluripotential state.

 Analysis of the lungs from these homozygous mouse embryos found that some Heparan sulphate species[19] were increased (D0A0, D0A6, D0S6/D2A6) whereas others were decreased (D0S0/D2A0, D2S0), indicating appreciable changes that could be expected to affect binding characteristics to ligands and receptors.

 

Of particular significance with the recent findings is that the Heparan sulphates formed in the Golgi are secreted from the cells and associate with the external (plasma) cell membrane, where they are modified (�fine tuned�) by the enzymes Sulf1 and/or Sulf2 before modulating a number of intercellular messengers, such as Wnt, FGF and Hedgehog. (Terms will be used generically.). These are particularly important in the embryo and can be involved in maintaining stem cell lines. The complex process is outlined in Figure 2.

 FIGURE 2

 

 

 

 

 

                                                                                                                   Genes/Chromosomes

 

                                                                                                                 gene transcription promoters                                                                 

                                                        GOLGI                                    TCL/LEF

                                                           Polysaccharide                                          

                                   Inhibited by                        Precursors

                                   Lithium                              gPAPP

                                                                   Heparans

                          Cell

                                (plasma)                   

                                     membrane                                            

                                                                                                          Stabilized b-Catenin

 

                                                                                                         Glycogen synthase kinase-3β

                                         Sulf1                                                           Inhibited by Lithium                                                                             

                   Other                                   Sulf1                                               

                     Receptors    Sulf2                                                                                                      

                                               Modified    Sulf2                                                                                                                        

                                              Heparans                                          Wnt Receptor (Frizzled)

                                                                     

 

 

                   Wnt 

                                                                                                                                              

 

Figure 2: A diagram to demonstrate the major points of the U-shaped cascade by which Lithium may affect cancers and some inflammatory conditions such as rheumatoid arthritis, lupus erythematosus and multiple sclerosis etc. Lithium suppresses the gPAPP enzyme (red) in the Golgi apparatus (lightgreen), resulting in modified Heparans (orange �lightning� symbol). These are secreted and attach to the extracellular surface of the cell�s plasma membrane. They are further modified by the Sulf enzymes (if that is possible for the Heparans that arrive already changed; dark red) and form modified or defective co-factors attached to the ligand (green) and receptor (pink) complex (Wnt-frizzled). Lithium also suppresses Glycogen synthase kinase 3b, which frees-up b-Catenin which, in the canonical pathway, moves to the nucleus and activates transcription promoters. The important point arrises when the Lithium level falls; the disturbed Heparans on the cell surface persist, blocking constitutional Wnt (etc.) signalling, yet the level of Lithium is insufficient to replace the absent Wnt signalling by providing a substitute action through suppression of GSK3b. The cell suffers stimulation deprivation, which would be expected to lead to reduced growth and proliferation, and may lead to apoptosis.  Other receptors (rose) are probably involved.
  

Not only could Lithium�s effects on gPAPP result in modulation of a number of key intercellular cytokines in embryo development, but the Wnt pathway in particular, may be subject to Lithium�s actions as well by Lithium�s inhibition of Glycogen Synthase Kinase-3b (GSK3b), interacting together with associated phosphatases and PI3K/Akt, interactions considered adequate to explain how the relatively Lithium-insensitive GSK3b could become sensitive to physiological concentrations of intracellular Lithium[20].

Thus, there is formed a U-shaped cascade of steps between the Golgi and the nucleus with at least two points sensitive to Lithium, one apparently, being quite sensitive. We can speculate that disturbances caused by Lithium-affected gPAPP may cause sufficient changes in the structure and degree of sulphation of the Heparan sulphates released into the extracellular space, so as to modulate the actions of the Sulfs[21]. The products of their actions then bind the receptor/ligand complexes, thereby controlling incoming signal transductions, the Wnt receptors being one such target.

Now, the strange alternate day treatment protocol may have found some scientific support �

Following the twin Lithium doses on day one of the Lithium Rx two day cycle, the surge will do two things that are relevant here :

1)    Lithium will block gPAPP, causing alterations in the binding and structural characteristics of the Heparan sulphates (and Chondroitin sulphates). The altered Heparans will move to the cell exterior, be processed by the Sulfs and bind to the cell surface, providing disturbed co-factor action with respect to the transduction factors, such as Wnt and FGF[22], and blocking activation of the receptor mechanisms. The impact of these changes would be expected to be relatively slow (perhaps 12 h), with the external cell coating probably lasting a day or two (or possibly more). During this interval, the Wnt and some other selected pathways would be blocked. Depending upon a number of factors, such as the degree of differentiation, the effective surface areas for cytokine/receptor function and the cytokine/receptors concerned, there may be variable times required for the disturbed Heparans to build-up on the cells membranes. This may explain why the degeneration found with patient PC took ~80 day to develop. 

2)    Lithium would inhibit GSK3b (we assume the claimed sensitizing factors operate), stabilizing b-catenin and activate gene promoter and transcription activities. This response would be quicker � but would  decay quickly also, with the inhibition of GSK3b falling away within hours.

As the Lithium level falls, the combined effects are (a) that the constitutional Wnt stimuli are cut off by the abnormal Heparans, and (b) uninhibited GSK3b  phosphorylates b-catenin priming it for destruction, meaning that the cell is effectively deprived of most Wnt/and other pathway growth factor stimulation � which may retard growth and/or create a situation a bit like anoikis, and precipitate stimulation-deprivation apoptosis. There may also be an inability for the tumour stem cells to maintain their embryonal, pluripotential-like roles, a weakness that may target the tumour stem cells specifically. The sensitivity of the tumour cells may be related inversely to the degree of tumour differentiation � the more undifferentiated and embryonal in type, the greater dependence upon growth factor cytokines, and therefore greater sensitivity.

Psychiatric patients taking long term Lithium would be expected to have the abnormal Heparans on the cell surfaces but, with maintenance Lithium and the inhibition of GSK3b, there would be continued maintenance of the pathway, with Lithium as a Wnt replacement.

Early in the 1990s, the belief that the Lithium fall may be the important stage in Lithium treatment was formed. The current hypothesis provides support for this.

Of course, there may be other combined effects, such as creating a misbalance so that the extrinsic death signals that induce apoptosis[23] may be favoured.

 

The 434 MHz UHF treatment. The tumour marker responses following this form of treatment were explained earlier by the Golgi being disrupted because of the halt in mitosis progression following-on from the heat to the centrioles. The few tumour marker responses seen to date with Lithium Rx would seem similar, and would be consistent with the disturbed Golgi hypothesis.  

 

Inflammatory Conditions. There has been note elsewhere on this website that Lithium may reduce the inflammatory activity of certain conditions, such as rheumatoid arthritis, lupus erythematosus, multiple sclerosis, sarcoidosis, Hepatitis C etc. Since all of these can be expected to involve cytokine cell-to-cell transduction signals, the rather non-specific nature of the disturbed Heparan sulphates created by gPAPP in the Golgi under the influence of Lithium would explain why the activity of these conditions may be reduced, if not put in remission, by Lithium.

 

Long-term effects of Lithium Rx. After some eight months of continuous Lithium Rx treatment by PC, no adverse side effects of any kind have been noted to date. We are left to assume that normal, non-malignant cells are not appreciably sensitive to the putative cytokine deprivations expected with the Lithium Rx.

 

Conclusion: Overall, three subjects with different malignancies have been treated with Lithium Rx, this being an alternate day protocol. All have had some changes which may be regarded as encouraging on a short-term basis. One subject had histopathology showing degenerative changes that could hardly be due to any other cause. Considering the simplicity, likely cost-effectiveness and relative safety, with only a potentially mild suppression of thyroid function, it might be used indefinitely to maintain remission. More subjects may wish to try the protocol[24] if and when other options are no longer attractive.

As a result of very recent scientific studies, the way in which Lithium may induce these effects may now be explained. There is still much more work to be done.

An essentially similar protocol had earlier been used on subjects with various inflammatory conditions, again with gratifying results. The actions of Lithium may well be essentially similar at a biochemical level.

We may look to Lithium to provide useful treatment for human malignancies and inflammatory condition for centuries to come.

                      

 Click to E-mail me with concerns about  CANCER, RHEUMATOID ARTHRITIS,
                                                                                    LUPUS ERYTHEMATOSUS,

                                                                                    MULTIPLE SCLEROSIS,
                                                                                    SARCOIDOSIS, HEPATITIS C, etc

                                                                                                          also
                                                                                   INVESTIGATIONS, DIAGNOSIS & TREATMENT

 

Malcolm Adams Traill

Copyright � MA Traill 18 January 2009


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[2] Anderson KC, in �Cancer Medicine,� (�Holland & Frei�) Editors:  RC Bast, DW Keefe, RE Pollock, RR Weichselbaum, JF Holland and E Frei; 5th Edition; p. 2074 

[3] Edwards CM Edwards JR et al. Blood 2008; 111:2833-2842

[4] Cl�ment-Lacroix P Ai M et al. Proc. Natl. Acad. Sci. USA. 2005; 102(48):17406-17411

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[6] Cohen Y Chetrit A et al. Med. Oncol. 1998; 15(1):32-36

[7] www.radiowaveclinic.com

[8] www.malsmusings.info Chapters �Holt�s Cancer Treatment, the Centriole and Herbert Fr�hlich,� �The Centrioles in the Retina andThe NH&MRC Review � Dissection.�

[9] www.malsmusings.info Chapters �Treatment

[10] Dimopoulos MA Kastritis E et al. Leukemia 2008; 22(8):1485-1493

[11] Golgi apparatus: Camillo Golgi, 1843-1926, Italian Histologist; shared Nobel Prize in 1906

[12] Morris JC & Holland JF, in �Cancer Medicine,� (�Holland & Frei�) Editors:  RC Bast, DW Keefe, RE Pollock, RR Weichselbaum, JF Holland and E Frei; 5th Edition; p. 2447-8 

[13] Tietz NW Siggaard-Andersen O et al. in �Textbook of Clinical Chemistry,� Ed. NW Tietz, WB Saunders Company, Philadelphia, 1986; p. 1251.

[14] Furusho K Kamiya T et al. Lancet 1984; 2(8411):1055-1058 

[15] �The Merk Manual;� 14th Edition, Editor R Berkow; Merk Sharp & Dohme Research Laboratories, New Jersey, 1982; p. 281, Table 16-1. The type of fall (linear or not) is not given.

[16] Frederick JP Tafari AT et al. Proc. Natl. Acad. Sci. USA 2008; 105(33):11605-11612

[17] www.malsmusings.info Chapter �Prostate Cancer and Lithium � a Therapeutic Renaissance ?

[18] Sasaki N Okishio et al. J. Biol. Chem. 2008; 283(6):3594-3606

[19] Lawrence R Lu H et al. Nat. Methods 2008; 5:291-292

[20] Jope RS. Trends Pharmacol. Sci. 2003; 24(9):441-443

[21] Holst CR Bou-Reslan H et al. PLoS ONE 2007; 2(6):e575

[22] Lamanna WC Frese M-A et al. J. Biol. Chem. 2008; 283(41):27724-27735

[23] Jope RS Yuskaitis CJ et al. Neurochem. Res.2007; 32(4-5):577-595

[24] www.malsmusings.info Chapter �Your Cancer & Lithium Treatment