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. 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 a compound was found with such a required quality.
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 new compound is activated outside the cancer cell, i.e. the genetic machinery does not realize the attack, and secondly, the drug doesn't enter the cell, but only penetrates into the cell membrane. It becomes incorporated in the cell membrane, thereby creating pores into the membrane. 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, which cannot be genetically manipulated or counteracted in contrast to the "inside" attack of currently used procedures.
The "magic" compound to enable this procedure is Diflunisal, an approved anti-inflammatory drug. The characteristic features are not provided by Diflunisal alone but only by the assistance of a second compound, synergistically supporting the actions. This supporting function can be provided by two more salicylates, which are approved drugs as well, namely ASA (Aspirin, Aspisol) or PAS (p-aminosalicylic acid, a tuberculo-static drug). The medicament, therefore, consists of synergistically acting combinations of Diflunisal and ASA or PAS. These synergistically acting combinations are protected by several patents.
Comparisons with current cancer therapies
In the field of cancer therapy there are various different strategies which can be evaluated according to their effectiveness and selectivity.
One of the common strategies aims at the characteristics of the cancer cells, which differ from those of normal cells. These target characteristics are for instance higher proliferation rate or enhanced signal transduction. The possible therapy effect in these cases is substantially limited, since these target characteristics can only be reduced to the level of the normal cells. By exceeding this level, this type of cancer therapy will also damage normal tissues, in other words, there may occur extensive side-effects. Therefore, with these methods complete cure of cancer is impossible.
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 have to 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.
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 lowers 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.
These findings mean a spectacular progress in cancer therapy, providing a solution for an effective treatment of all kinds of tumors and metastases. Moreover, the therapy procedures should accomplish complete remission of the tumors. It should be pointed out that the administration of ASA alone is not successful in combating cancer cells because ASA also stimulates proliferation of cancer cells in acidic as well as in basic milieu. Therefore, if ASA is applied as stimulant for the immune system, at the following 3 days ASA- Diflunisal combinations or Diflunisal -PAS or ASA-PAS combinations have to be administered for eliminating acidic tumor fractions.