Bless!

In a recent digest, Cedric discussed the problem of tumour lysis. Tumour lysis occurs, when cancer cells die in the toxic and highly inflammatory cell death mode of necrosis, which in severe cases can lead to multiple organ failure and death of the patient.¹

It goes without saying, that tumour lysis must thus be prevented, lest treatment trying to heal the patient inadvertently kill them.

Today, I want to talk a bit about why tumour lysis doesn't happen in all cancers and about what we can learn from this about the prospect of stopping cancer cells from necrotising by shifting their death mode toward apoptosis instead. Those are all big words, but don't worry, I'll break them down as they become relevant to the topic at hand, for knowledge is only ever transformative, if it can be transferred from one mind to another.

Why Tumour Lysis Doesn't Occur in All Cancers

Tumour lysis is a process of uncontrolled cancer cell death, where the cells in question buckle under stressors, to which they for some reason can't respond appropriately. There are two primary requisites for tumour lysis to occur:

1. The cancer cell must be under lethal duress.
2. The cancer cell must be incapable of initiating apoptosis, in response to this duress.

This is also why tumour lysis doesn't occur in all cancer and all patients – in fact, it most often occurs in haematological cancers.¹ Firstly, tumour lysis needs an effective treatment for the cancer at hand, which most patients are sadly left without. Secondly, the treatment must be applied to a cancer cell, which can't initiate apoptosis.

Apoptosis is an orderly process of sacrificial cell suicide, which healthy cells will so routinely engage in, that about half of all neuronal cells generated during embryogenesis (development of an embryo) apoptose.^2–3 During apoptosis, the self-sacrificial cell will digest its own internal components and package them into neat membrane-bound droplets, which macrophages may take up and transport off without much effect upon the surrounding tissue. Apoptosis is generally good and not worrisome.

Now, cancer cells unable to initiate apoptosis still must die, when under lethal duress, as that is the very definition of lethal duress. As they are unable to digest and package their contents in an orderly fashion, they instead die in a lytic cell death, where the cell membrane ruptures and its contents spill out into the extracellular space.³ The prototypical consequence of lytic cell death is necrosis, and the spillage it causes is toxic and highly inflammatory.

In a starkly simplified way you may think about apoptosis and necrosis in the following way:

1. As a cell comes under duress, it will first try to ameliorate the source of this duress.
2. If it can't do this and can't rescue itself, it will go into apoptosis.
3. If it can't go into apoptosis for one of a countless possible reasons, it will survive the duress until it becomes unsurvivable and will then die not of an orderly suicide, but of a violent, disordered death, resulting in necrosis and the toxicity to the surrounding tissue.

When this happens en masse amongst the cells of one or multiple large masses of cancerous tumours, because treatment is sufficiently lethal to these cells, the resultant ailment of the patient is then called tumour lysis syndrome (TLS), which can be lethal to the patient.

What We Can Learn From This

TLS occurs primarily due to some form of apoptotic incompetence, which prevents orderly sacrificial suicide of the affected cancer cells prior to acute lethality of the treatment. This also means, that hypothetically TLS could be prevented by restoring apoptotic competence to these cancer cells.

Now, obviously restoring such apoptotic competence to cancer cells expert at not dying is quite difficult. At this point, we're attempting to formulate such a regimen in order to suppress tumour lysis in one patient without having to stop killing cancer cells. After all, we'd very much like to kill all of them, just by different means. If this regimen turns out successful, we'll naturally add it to the upcoming written guide on the Mosaic Method, described in more detail there, and in a separate digest and/or report.

The very fact, that some cancer cells are susceptible to apoptosis and will rather die normally than necrotise to me seems an indication, that it's theoretically possible to modulate signalling pathways also in apoptosis-resistant cancers to allow them to kill themselves in an orderly fashion. Whether this is true, remains to be seen, but let's take a look at what I found in literature.

Many Roads Lead to Rome

Primarily, it seems, that cancer cells will prevent their own apoptosis by expressing anti-apoptotic proteins in such vast quantities, that no matter the damage they incur, they won't be able to kill themselves.

Some of the common problem children in apoptosis-resistant cancers – which oftentimes also happen to be highly treatment-resistant as they can take a lot more of a beating without inadvertently killing themselves – are the specific related proteins Mcl-1, Bcl-xL, and Bcl-2, as well as XIAP and survivin.

The difficulty we have in simply counteracting these anti-apoptotic proteins, is that they are essential to the survival of some of our healthy cells. So, for example is Bcl-xL activity required for the persistence of thrombocytes (platelets) in the blood. Treatments, which simply diminish Bcl-xL activity have caused thrombocytopenia (the suppression of thrombocyte counts). As this is rather suboptimal, I've elected to look for other ways of effectuating the re-emergence apoptotic competence.

To do this non-toxically I found it most intuitive to look at pharmaceuticals, which may destabilise the above anti-apoptotic proteins or modulate their production and/or clearance.

There are several ways of doing this. We know for example, that oxidative and endoplasmatic reticulum (ER) stresses may initiate apoptosis even when the cell is highly expressive of anti-apoptotic proteins. Oxidative stress happens, when a cell is exposed to too large a quantity of oxidants. ER stress can occur by various means, including extended oxidative, heat, and osmotic stresses. Not all of these stresses can be feasibly used safely within patients.

Cancer tumours are naturally highly hypoxic (meaning they have extremely low oxygen), which should make the incitement of oxidative stress rather easy in cancer cells, compared to healthy cells, as the former are far more adapted to low-oxygen environments and would be expected to be unable to handle high-oxygen environments. Whether this be true, we'll discover below.

The susceptibility of some cancers to heat – or more accurately, their susceptibility to misfolded proteins and mineral imbalances – is also at least theoretically exploitable. In how so far that can be done, we'll explore below.

Alternatively, some cancer cells under treatment duress may also be in energy crisis and thus unable to go through apoptosis, as it is an energy dependent process.³

Chlorine Dioxide

Chlorine dioxide is the compound on this list with the single longest track record for human use, as it's used in drinking water treatment and widespread as a self-administrated medication in low-income countries for treatment of various diseases, whose standard treatments in higher-income countries would simply be impossible to purchase for the affected individuals. I'll leave this tragic failing toward our less fortunate brethren without comment, as it would indubitable have me ramble on for far too long.

In any case, chlorine dioxide is a powerful and seemingly selective inducer of cancer cell apoptosis.⁴ It's furthermore been used in humans with success.⁵ Though one of 6 patients died after they stopped feeding themselves post-relapse. The authors sadly don't state, whether the relapsed patient continued use of chlorine dioxide up until death, or whether suspension of chlorine dioxide treatment may have played a role in relapse.

A benefit to chlorine dioxide is that its chemistry with biological structures differs significantly with acidity.⁶ At alkaline or neutral pH values – as those of healthy tissues in metabolically healthy humans –, chlorine dioxide acts as a very mild oxidant, which is not expected to change the morphology or even the redox balance of metabolically healthy cells significantly.^7–8 At acidity – as can be found in tumours –, chlorine dioxide reacts differently and fully oxidises certain amino acid residues in proteins thus modifying them in a way, that may cause a cessation of their function.

Nonetheless, as with every intervention in the Mosaic Method, the treatment with chlorine dioxide alone can never be expected to heal a patient. Neither can the treatment with all available therapeutics ever be guaranteed to heal everypatient. That's sadly not how stochastic processes work, but that's a discussion for another time.

No reports exist for death from oral exposure to chlorine dioxide.⁹ An oral dose, where 50% of mice perish, sits somewhere above 10 g/kg of body weight. To put that into perspective: Chlorine dioxide is usually purchasable as a 0.3% stock solution. Even assuming, that humans are 10-times more susceptible to chlorine dioxide poisoning, which we from all indication aren't, you'd have to drink 330 mL of that stock solution to approach this lethal dose 50.

However, one of the ways chlorine dioxide is produced includes chlorite in its reaction substrates. Chlorite is about 100-times more toxic than chlorine dioxide itself. This means, that if the chlorine dioxide is produced with the above method and the stoichiometry is off, the tainted stock solution may indeed be far more dangerous than is expected of untainted aqueous chlorine dioxide.

Furthermore, high consumption of chlorine dioxide may cause methaemoglobinaemia, which is a serious ailment needing treatment. Thus, as with every single pharmaceutical treatment in existence, intelligent use and medical monitoring is essential.

On the anecdotal front, we have precursory data from its successful use in one patient to stop tumour lysis. As the amount of apoptotic activity is yet unknown, we'll publish a report in the future as a follow-up, when more precise data makes itself obvious. At this moment, it tumour lysis seems overcome, the next issue to be tackled in the patient now being the clearance of apoptotic vesicles (self-packaged debris from apoptotic cells). We will publish another essay on that matter, though.

Future Potential

There admittedly isn't a whole lot of research into resolving tumour lysis at its root, namely the apoptotic incompetence of cancer cells, which leads to necrosis. Resolution of tumour lysis isn't much a field of research, because whilst it's a serious clinical condition, very few patients have the luxury of a treatment modality effective enough at killing cancer cells as to ever expose them to the dangers of tumour lysis.

Apparently, the Mosaic Method as we've deployed it in one patient was so potent in causing lethal duress to cancer cells, that tumour lysis syndrome became an issue in mesothelioma for the second time in recorded clinical history (from what I could find).¹⁰

And the specific challenge of overcoming or simply circumnavigating over-expressed Bcl-xL, as was our approach, seems also to be almost non-existent in the literature. Nonetheless, as future research accumulates such pharmaceuticals as betulin from birch bark, celastrol from thunder duke vine, and falcarindiol from carrot may indeed prove to be highly helpful in counter-modulation of Bcl-xL and Mcl-1 in cancer cells, though that still remains to be seen.^11–14

Conclusions

It seems broadly possible to lower the apoptotic threshold in overly death-resistant cancer cells in order to prevent necrosis and resultant tumour lysis syndrome. In one patient, apoptotic instead of necrotic cell death seems to have been inducible by use of chlorine dioxide, though long-term data is needed to draw any amount of a solid conclusion.

Furthermore, even in overcoming tumour lysis syndrome, the development of oedemata and effusions may still be a hinderance to patient quality of life and intensity of treatment, as apoptotic vesicles may indeed still draw water by increasing the oncotic pressure of tissue serum (basically the apoptotic vesicles act somewhat like enormous water-drawing salt particles, drawing water from the blood into the extracellular space).

Proper clearance of such apoptotic vesicles and thus the prevention of oedema and effusion development become the next important step to successfully manage patient health, treatment, and wellbeing. As stated before, another essay shall tackle this matter in the future.

I hope this has been informative and interesting to read. At the end of the day, I think this essay above anything should act as a light of hope. Tumour lysis syndrome is so uncommon, because effective treatment regimens of cancer are so likewise. That the patient even experienced tumour lysis without prior toxicity or negative of the treatment to me seems like an enormous boon, for it is indicative of an extreme differential of the effect of the Mosaic Method on cancer cells vs. healthy cells.

If tumour lysis can be effectuated in terminal-stage mesothelioma, then patients suffering from other types of cancer have hope too.

Toward a cancer-free future, I hope.

God bless,
Merlin L. Marquard