Meta-analysis of the role of p53 status in isogenic systems tested for sensitivity to cytotoxic antineoplastic drugs.

ABSTRACT

The role of p53 in modifying sensitivity to cytotoxic drugs has been commonly studied by creating transfection pairs of wt p53 parental cells and altered p53 daughter cells, or vice versa. Authors inevitably tended to extrapolate and generalize their experimental observations, and conflicting reports have been more the rule than the exception. We have performed a meta-analysis of 356 independent studies. Average changes of drug sensitivity after a change of p53 status were observed. E6 transfection predominantly induces sensitization to cytotoxic drugs, whereas p53-/- knockout cells are more drug-resistant than their normal p53+/+ counterpart. Unexpectedly, transfection with a mutated p53 does not change much the drug sensitivity of most wt p53 cancer lines, with the notable exception of A2780, a predominant cell line in the studies analyzed (A2780 cells show increased resistance after transfection with a mutated p53). Rather interestingly, mitotic spindle poisons acted differently from other classes of cytotoxic drugs. A crucial indication of our findings is that the role of p53 alone in determining sensitivity/resistance to cytotoxic drugs is limited the individual molecular pathology and differentiation of a given cancer line prevail over any average trend, and are causal to a broad spreading of the data. We also identify major "confounding factors", alias independent categorical variables, capable of affecting the average outcome.