During the past days I was “forced” to go back to 3BP and think more about it in the context in which I hear more and more about people who are responding but even more important people not responding (out of which some very good friends …).
Actually, when I hear about patients/friends not responding to 3BP, I start to loose my trust in 3BP but than I went back to our file and saw the response so clear in the blood test in our case, during every cycle of 3BP we had (response to one cycle even visible on CT). And than the trust comes back and with that the question WHY? [Note, now we are using Diflunisal (next to many others including some immunotheraphies), which seems to show response. After the Diflu cycle, we will probably go back to 3BP if appropriate and depending on what my wife likes]
In the end, we are battling the challenge of humanity, i.e. cancer. Fighting in a field where the conventional medicine of this world could not help us … and so far successfully.
Back to the question WHY. I know that this question is constantly in the mind of some great scientists involved in the 3BP research. Why some people are responding and some not? Of course, there can be so many explanations, that include blood type, tumor perfusion, MCT expression, 3BP administration strategy and stability of the specific formulation … and so on … However, I feel the main answer is connected to the following statement I came across while reading some patents on Diflu: “Thus each type of tumor has an intrinsic average intercellular pH, which, for example, in the case of breast tumors is about 6.7 and in the case of colon tumors about 6.9.” Ref
The interesting point is that this statement or piece of information may be the right link between two facts:
- A pattern that seems to emerge from all the outcomes we hear of following 3BP treatment, i.e. most of the responding patients are breast cancer patients. (And many of which are simply using the oral administration strategy mainly.) Next to that one prostate, one melanoma, one adrenal, one lung, one pancreas, two liver (but these liver cases were TACE which may be seen as forced and direct administration and should not be compared to the others – my personal opinion). I am not sure about others but at least this is what comes to my mind in terms of most relevant cases.
- Recently, we have seen an article published stating that 3BP transport is higher when the extracellular milieu is acidic:
The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH:At pH6.0, the affinity of cancer cells for 3BP transport correlates with their sensitivity, a pattern that does not occur at pH7.4. In the three cell lines, the uptake of 3BP is dependent on the protonmotive force and is decreased by MCTs (monocarboxylate transporters) inhibitors. In the SK-BR-3 cell line, a sodium-dependent transport also occurs. Butyrate promotes the localization of MCT-1 at the plasma membrane and increases the level of MCT-4 expression, leading to a higher sensitivity for 3BP … We find that the affinity for 3BP transport is higher when the extracellular milieu is acidic. This is a typical phenotype of tumour microenvironment and explains the lack of secondary effects of 3BP already described in invivo studies [Ko et al. (2004) Biochem. Biophys. Res. Commun. 324, 269-275].
Yes, while it needs to be investigated further, it is probably the extracellular pH that makes the difference. And breast cancer seems to be one that is characterized by an even lower extracellular pH and this may facilitate the transport of 3BP inside the cancer cells. What are the other cancers characterized by an more acidic tumor environment? That remains to be further investigated. However,this could be a way to select patients that are likely to respond to 3BP treatment. Since the extracellular pH is inverse proportional with the glycolysis (i.e. the higher the glycolisis, the lower the extracellular pH will be) a simple way to identify potential respondents to 3BP is to use PET scan intensity as a reference (however, as discussed here, we need to remember that in my view besides low extracellular pH there is a need for Oxygen as well in order to have the cancer cells able to be fueled by lactate).
Yes, MCT transporters are highly dependent on pH. Transport rates are increased over 10-fold by lowering the pH one unit from 7.4 to 6.4. (Ref.) And as we know, the transporters used by 3BP to enter the cancer cells are the MCTs.
As discussed in other 3BP-related articles on this website, getting response is the first challenge. Maintaining that is another challenge that needs to be addressed together with other drugs, including angiogenesis inhibitors and glycoinhibitors.