The role that glutathione S- transferases (GST) play in the protection of
tumour cells from cytotoxic insult was investigated. The possibility that GSTs
may be involved in a stress- response was also explored.
Derived drug-resistant tumour cell lines as well as showing various
changes commonly associated with drug resistance, also show overexpression
of certain GSTs. In the majority of drug resistant tumour cell models however,
the ability of the drugs against which resistance is seen to act as GST substrates
has not been demonstrated. For this reason, the known GST substrate, 1-
chloro-2,4-dinitrobenzene (CDNB) was used to generate a tumour cell line
resistant to this compound. The resultant CDNB resistant lung tumour cell line
(CDNBr) exhibited marked overexpression of both alpha and pi class GST
subunits. This cell line was also resistant to cumene hydroperoxide, a substrate
for alpha class GST. However, no resistance to any of the anticancer drugs
studied, was observed. The results demonstrate that the GSTs can protect cells
against cytotoxic insult from certain alkylating agents and hydroperoxides and it
is possible that the GSTs are involved in some sort of chemical stress response.
However, in the CDNB resistant lung tumour cell line, GSTs do not appear to
provide protection against a broad spectrum of anticancer drugs.
The role of the human class pi enzyme in the resistance of human
leukaemia cells to antitumour agents was also investigated. The results of this
show that in certain instances, the pi class enzyme may be involved in resistance
mechanisms to a number of drugs including chlorambucil. This work however,
highlighted the multifactoral nature of drug resistance.
In conclusion, although the GSTs certainly appear to have the capacity
to protect cells from cytotoxic compounds, it is evident that they are not the
sole factor which determines the response of tumour cells to drug treatment.