Healthy Living Forum

While a number of effective chemotherapies are available, tumors inevitably evolve resistance to these drugs ultimately resulting in treatment failure and cancer progression. Causes for chemotherapy failure in cancer treatment include poor blood supply to the tumor, low tumor oxygen concentrations, and resistance to drug-induced toxicity through up-regulated metabolic pathways or DNA repair mechanisms.

Unless a cytotoxic therapy eradicates all cancer cells, its application to a tumor population also produces evolutionary selection forces that will select for cells that are adapted to the therapy and, thus, fittest to these conditions. In fact, this mechanism has been used to produce many chemo-resistant cancer cell lines.

A fundamental principle of chemotherapy is to use drugs that are more toxic to tumor cells than to healthy cells, the preferred target being the cancer cell replication mechanisms, as many tumors replicate faster than the host. Unfortunately, tumors are not homogenously proliferative. Typically, only its outer rim is composed of replicating cells, while much of its inner mass consists of cells in quiescent or even dying states.

 Thus, the cells on the outer rim of the tumor are the most readily targeted by chemotherapy due to their proximity to blood vessels and their fast growth. This region of the tumor is thus environmentally sensitive and is mostly composed of chemotherapy-sensitive cells, even though some resistant cells may be present.

The inner regions of a solid tumor are often hypoxic (low oxygen concentrations) and acidic due to anaerobic glucose metabolism (feeding rapidly on sugar), which leads to quiescence and increased chemo-resistance. The increasing distance from blood supply reduces the concentration of chemotherapy in these regions of tumor, conferring a second cause for resistance.

Metronomic Fractionated Chemotherapy

The definition of metronomic fractionated chemotherapy varies, but generally it refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium (which will form new blood vessels) or tumor stroma (abnormal connective tissue that feeds the cancer) as opposed to targeting the tumor. The metronomic approach was initially proposed and tested in animal models by Dr. Timothy Browder in Dr. Judah Folkman's lab at Harvard Medical School. In the studies, standard maximum-tolerated dose (MTD) chemotherapy regimens caused cell death of endothelial cells in the blood vessels feeding to the tumor first, followed by tumor cells. But the long breaks needed between the MTD regimens allowed the damaged blood vessels, and thus the tumor, to recover.

But significantly lower doses given more frequently on a prolonged schedule proved to be far more effective, including complete tumor regressions, even in mice that were resistant to the same drug when used in a standard MTD regimen. Since then, several research groups have confirmed these findings. Therefore, the advantages of metronomic fractionated chemotherapy appear to be lower toxicity, inhibition of angiogenesis (inhibits development of blood vessels that will feed the tumor), and possibly less resistance due to more frequent administration.

Cancer pH Manipulation Therapy

Metronomic fractionated chemotherapy may be an effective method for treating the outer rim of the tumor, with minimal toxicity, but what about the inner mass, that is anaerobic, hypoxic, and lacking blood supply? Using a technique called Cancer pH Manipulation Therapy, in combination with metronomic fractionated chemotherapy, it may be possible to eradicate both the inner and outer core of the tumors. As stated above, the inner core of tumors relies on glucose for energy. The end product of glycolysis (the method for processing glucose into energy) is lactic acid. Tumor cells in the inner core produce a large amount of lactic acid, which then must be pumped out of the cell. Pumping acid out of the cell serves two purposes:

1. The cancer cell avoids cell death from overwhelming acidosis.
2. The acid that accumulates outside the cancer cell (after it has been pumped out) promotes the further aggressiveness of the cancer.

Using a cocktail of oral drugs, it is possible to halt the cancer cells’ ability to pump out its own acid. This technique will cause the “inner core” cancer cells to die due to severe acidosis. Combining Cancer pH Manipulation with Metronomic Fractionated Chemotherapy we may be able to eradicate not only the rapidly dividing outer core cells, but the inner core cancer stem cells as well.

Mark A. Rosenberg, M.D.

06/22/2012