title: Apoptosis, p53, and tumor cell sensitivity to anticancer agents.
abstract: A widely held tenet of present day oncology is that tumor cells treated with anticancer agents die from apoptosis, and that cells resistant to apoptosis are resistant to cancer treatment. We suggest, in this review, that this tenet may need to be reexamined for human tumors of nonhematological origin, for two principal reasons: (a) cell killing has often been assessed in short term assays that are more influenced by the rate, than the overall level, of cell killing. This has tended to underestimate cell killing for cells not susceptible to apoptosis or having mutant p53; and (b) conclusions from experiments with normal cells transformed with dominant oncogenes have often been extrapolated to tumor cells. This does not take into account the fact that tumor cells have invariably undergone selection to an apoptotically resistant phenotype. In this review, we examine the impact of these two factors with particular emphasis on the influence of mutations in p53 on the sensitivity of tumor cells to DNA-damaging agents. We find that because wild-type p53 predisposes cells to a more rapid rate of cell death after DNA damage, particularly with normal or minimally transformed cells, that short-term assays have led to the conclusion that mutations in p53 confer resistance to genotoxic agents. On the other hand, if clonogenic survival is used to assess killing in cells derived from actual solid human tumors, then apoptosis and the genes controlling it, such as p53 and bcl-2, appear to play little or no role in the sensitivity of these cells to killing by anticancer drugs and radiation.
authors: Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5468, USA.
authors: J M
authors: JM
authors: Brown
authors: B G
authors: BG
authors: Wouters
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D019254:Genes, bcl-2; D016158:Genes, p53; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D004247:DNA