Based on the pH-sensitive, synergistic acting combinations of salicylic acid derivatives
The newly developed cancer therapy opens up the chance for generally combating cancer cells without causing side effects due to its high selectivity because it is based on the very well established fact that tumors and metastases are acidic in their extracellular aqueous environment, which offers an ideal target to selectively attack cancer cells by pH-sensitively acting drugs.
therapy method was developed by Prof. Dr. Werner Kreutz (see Curriculum Vitae)
at the Institute of Biophysics and Radiation Biology (since 2000 converted
to Centre for Neuroscience), Univ.
This therapy method was developed by Prof. Dr. Werner Kreutz (see Curriculum Vitae) at the Institute of Biophysics and Radiation Biology (since 2000 converted to Centre for Neuroscience), Univ. Freiburg, Germany.
Features of the therapy
· A novel cancer therapy that is effective on all solid tumors and metastases.
· Very effective on cancer cells, yet not toxic to healthy tissues
· Based on a novel target principle with pH-dependent reactions of the active ingredients on cancer tissues, thus avoiding side effects on healthy tissues
· More than 150 patients in advanced stage without any other therapy option have been treated successfully so far, including numerous complete remissions
· Induces apoptosis (cell death) and pore-formation on the cancer cell membrane, preventing genetic adaptation and defense mechanism of cancer cells.
· Well tolerated by patients. The drugs are administered in relatively small doses intravenously in defined time intervals.
· Combinations of salicylic acid derivatives. All active substances (APIs) used in the therapy are approved drugs for other diseases ("Off-label-use”).
· Induces immune response, as well
Based on the notion that the extracellular milieu of cancer cells is acidic in contrast to the basic external milieu of normal tissue we developed a new strategy where cancer cells cannot escape. The acidic pH of the extracellular environment which is specific to the cancer cells is now the target parameter against the cancer cells.
Combinations of pH-sensitive salicylic acid-derivatives are given intravenously. At physiological pH they are transported as polar salts in the patient’s blood. In the acidic microenvironment of tumor cells, they are selectively activated and in the protonated state exert their cytotoxic activity by pore-formation in the membrane, by inhibition of energy supply and by induction of cell death (apoptosis).
Since both solid tumors and metastases can be eliminated by this pH-sensitive method, there is a good chance of healing cancer. Also, there is no considerable side effects because of the high selectivity of this method.
This method is made possible through three synergistically effective salicylate-combinations (NSAIDs):
Diflunisal – PAS (p-Aminosalicylic acid)
Diflunisal – ASA
ASA – PAS
Diflunisal (anti-inflammatory, anti-rheumatic drug), ASA (Aspirin, Aspisol), and PAS (p-aminosalicylic acid, a tuberculo-static drug) are commonly known, approved drugs. These synergistically acting combinations are protected by several patents
What makes the difference to currently practiced cancer therapy methods?
The new target for cancer cell attack
The exclusive quality of cancer cells in tumors as well as in metastases that their extracellular milieu is acidic in contrast to the basic external milieu of normal tissue, represents an ideal target to combat cancer cells selectively without attacking normal tissue. The ideal anti-cancer drug then should become toxic as soon as it enters the acidic milieu, and only then.
In a research work lasting about 20 years at the Institute of Biophysics of the Univ. Freiburg (Univ. clinics of Freiburg) a compound was found with such a required quality (see The scientific basis).
The new way of killing cancer cells
Current therapy strategies are based on cell functions which differ in cancer cells from normal cells and which are lastly genetically managed inside the cell. Principally those deviating functions from normal cells can only be reduced down to the level of normal cells by anti-cancer drugs. By continuing this procedure it will also attack normal cells, i.e. causing commonly known side effects. Also, counter action by genetic adaptation or other attack escape strategies of cancer cells may be involved.
With the new method these difficulties are avoided because of two reasons: firstly, the synergistic combinations of salicylates doesn't attack the normal cells due to their pH-sensitive activation, and secondly, they are activated outside the cancer cell, i.e. the genetic machinery does not realize the attack since these drugs don't enter the cell, but only penetrate into the cell membrane, thereby creating pores. These porous structures will lead to breakdown of the membrane gradients, thus inducing cell death.
Facit: the new strategy is based on an "outside" attack at pH ≤7.0 (normal cells have pH ≥7.3), which cannot be genetically manipulated or counteracted in contrast to the "inside" attack of currently used procedures.
Comparison with other current approaches
In the field of cancer therapy there are various other strategies which can be evaluated according to their efficacy and selectivity.
In case of the so-called angiogenesis-inhibition, its strategy is to impair the development of the blood supply vessels of the tumors. Thus, one hopes to cut off the energy supply to the cancer cells. Two objections must be made in this respect. Firstly, already existing blood vessels are not affected by this method, and secondly, it is a fact that the tumors, at least in the periphery, can survive without blood supply. These peripheral areas of tumor are also the ones with highest proliferation rate. It is probably the case that the angiogenesis-inhibition induces the tumors to enhanced invasive activity and to enhanced metastasis (see also: Robert J. Gillies et al. “Acidity Generated by the Tumor Microenvironment Drives Local Invasion”, http://cancerres.aacrjournals.org/content/73/5/1524.long).
Completely different aspects are to be considered in case of the antibody therapy and cancer vaccines. There is a crucial barrier for the immune system to be successful against cancer cells: the tumors lower the pH-value of their intercellular space to acidic pH-value of 6.5 - 7.0 and places their proliferation optimum at pH 6.8, whereas the pH-value of normal tissue is at 7.4. This is a crucial reason why cancer cells can survive despite of the human immune system.
Immune defense encompasses in principle two different aspects: one is “to identify“ and the other is to “to kill“ or “to eliminate“ the cancer cells. Extensive research activities in our Institute came to the result that all four known kill-mechanisms of the immune system are pH-dependent (see Publications).
The pH-inhibition starts at pH <7.0. This primarily means that, even if the cancer cells are identified by the immune system, they cannot be eliminated because of its acidic environment. Since tumors consist of up to 80% of acidic tissues, these tumor parts cannot be influenced substantially, even if one succeeds to activate antibodies at pH 7.2 - 7.4.
In other words, even if one succeeds to overcome the protection factor (“immune checkpoint blockade”) in the alkaline area, fundamental barriers are installed against the immune system. Therefore, immune therapy against cancer can only be partially successful. Namely in so far, as the cancer cells proliferate and stay in alkaline interstitial environment.
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© 2019 Prof. Dr. W. Kreutz, Krozingerstr. 3 (Am Schlossberg), 79214 Staufen, Germany