Glutathione with Chemotherapy | Part 1

The concern about the use of glutathione with
chemotherapy is that it is an intra-cellular antioxidant that – in some
laboratory studies – appears to block certain effects of chemotherapy drugs in
cancer cells.  Specifically, the
naturally produced glutathione in cells can stop apoptosis, or cancer cell
suicide, from occurring. It is also associated with drug resistance to
chemotherapy in cancer cells. This is
certainly a concerning possibility. However, the extracellular application of glutathione, which is what
would happen when glutathione is given to a cancer patient by infusion, has a
different effect from the naturally occurring intracellular glutathione that is
involved in cancer resistance. 

The effects of extracellular glutathione were
investigated by, among others, Paolo Perego. In a study published in 2000), for instance, Perego and colleagues
applied extracellular glutathione to ovarian cancer cells. Two different lines of ovarian cancer cells
were used; one was chemotherapy–sensitive and one was
chemotherapy-resistant.  In control
cells, with no glutathione, the apoptosis rate was about 3% in the
chemotherapy-sensitive line. With
glutathione added, the apoptosis rate was about 30%.  Glutathione was not effective in causing
apoptosis in the chemotherapy-resistant line. The investigators also found that adding glutathione in this
concentration caused the production of hydrogen peroxide, a well known free
radical that can cause apoptosis and DNA damage in cancer cells. Hydrogen
peroxide was also shown to cause apoptosis in the chemotherapy-sensitive cell
line, although not in the chemotherapy-resistant line. The conclusion of the study was that
extracellularly administered glutathione produces apoptosis and DNA damage in
cancer cells due to production of hydrogen peroxide. Production of hydrogen peroxide is important
since this will cause an oxidizing environment around the cancer cell, which
may predispose it to damage by chemotherapy drugs, as well as to
apoptosis. Previous work suggested that
hydrogen peroxide was produced by the action of a glutathione-related enzyme,
gamma-glutamyl transferase, on the administered glutathione. Ironically, it is suspected that the
chemotherapy-resistant line obtained its resistance at least in part due to high
intracellular expression of glutathione-related enzymes. 

One question is whether the concentration of
glutathione used in the study might have been higher than what would be seen
when glutathione is given to patients, and thus caused an abnormal or irrelevant
result. So, the dose used in this study
was compared to the standard dose used with a chemotherapy patient. This comparison suggested that the patient’s
blood levels of glutathione should be even higher than those used in this
study. 

Research is now indicating that many antioxidants
turn into pro-oxidants when given in high doses without other accompanying
antioxidants, especially in pro-oxidant microenvironments in the body. Intravenous vitamin C is thought to work in
this same way, and the research of Perego suggests the same thing may happen
with glutathione. However, these antioxidants typically do not harm normal
cells when given at these dosages for limited periods of time.