Lipoplatin, currently under phase III evaluation, is a novel liposomal
cisplatin formulation highly effective against
cancers.
Lipoplatin has eliminated or reduced the systemic toxicity frequently seen for
cisplatin. The objective of the present study was to determine whether the cytotoxic effect of
lipoplatin is dependent on the functional integrity of DNA mismatch repair (MMR), a post-replicative DNA repair machinery implicated in cell cycle control and apoptosis. Clonogenic data revealed a significant (P<0.05) 2-fold resistance to
lipoplatin of HCT116 human colorectal
adenocarcinoma cells lacking MLH1, one of five
proteins crucial to MMR function, as compared to MLH1-expressing HCT116 cells. In addition, MLH1-deficient cells were at least 3-fold less susceptible to apoptosis (DNA fragmentation) than MLH1-proficient cells. However, proteolytic processing of
caspase-3,
caspase-7 and poly(ADP-ribose)polymerase-1 following
lipoplatin treatment was comparable in MLH1-deficient cells and -proficient cells. Furthermore, MLH1-deficient cells retained the ability to attenuate cell cycle progression past the G2/M checkpoint following
lipoplatin treatment. In conclusion, our results indicate that the
lipoplatin-sensitive phenotype of MLH1-proficient cells correlated with increased apoptosis which may occur via
caspase-independent pathways. They also suggest that the integrity of MMR function is a relevant determinant accounting for the cytotoxicity of
lipoplatin. However, this does not seem to apply to lipoxal, a novel liposomal formulation of
oxaliplatin, because MLH1-deficient cells were as sensitive to lipoxal as MLH1-proficient cells.