Chromium - Induced DNA Damage and Repair - Metal Complex-DNA Interactions - page 470

apoptosis is enhanced by supplementation of cell cultures with ascorbate. 104,109 As
mentioned earlier, ascorbate is thought to be the major intracellular reductant of
Cr(VI) creating high-valent, highly reactive chromium intermediates. These studies
further the hypothesis that ascorbate, normally viewed as an antioxidant, may act
as a pro-oxidant in cells treated with Cr(VI).
One specifi c characteristic of lung cancers caused by Cr(VI) - unlike other lung
carcinogens - indicates that cells carrying MMR defi ciencies will be prone to becom-
ing cancerous. This characteristic is called microsatellite instability 110 and is associ-
ated with a complete loss of MMR activity. 111,112 Another unique characteristic of
Cr(VI)-induced cancers is that lung tumours from Cr(VI) cancer subjects retain a
wild-type p53 tumour suppressor gene. 113 Therefore, constant exposure to Cr(VI)
compounds may not be necessary for tumour formation, since one would thus
expect the p53 gene to accumulate a large number of chromium-induced mutations.
Cells lacking MMR show resistance to an initial pulse of Cr(VI). This would lead
to accumulation of a small number of lesions and adducts, and then the lack of an
MMR system would allow those cells to continue to generate spontaneous muta-
tions without exposure to additional chromium. A model has been developed by
Salnikow and Zhitkovich to explain how MMR defi cient cells may actually be
selected following exposure to hexavalent chromium compounds (Figure 17.12). 113

Cr(VI) Exposure

Formation of Cr-DNA Adducts

MMR Proficient Cells MMR Deficient Cells

G2 Cell Cycle Arrest Apoptosis Resistance

Apoptosis

Cell Replication

Tumour Formation

Figure 17.12 Selection scheme for developing a pool of MMR-defi cient cells that may
explain the induction of a cancerous phenotype from chromate exposure 113