ABSTRACT
Apoptosis is a powerful cellular defense against cancer development. This
conclusion has derived largely from studies of the tumor suppressor gene p53.
Not only do a large majority of human cancers have either mutations in p53 or
defects in the pathway, but p53 null mice are highly prone to developing cancers
(1) and this is correlated, at least in some cases, with loss of the apoptotic
function of p53 (1). So important is this inactivation of apoptosis to cancer
development that evasion of apoptosis is considered to be one of the six fun-
damental hallmarks of cancer (2). The argument is then made that if apoptosis is
the important mode of cell death following cancer treatment, then inactivation of
apoptosis during tumorigenesis would be expected to render tumors resistant to
treatment with anticancer agents. Though this is a powerful argument made by
numerous observers, it is certainly not absolutely or universally true as both
experimental and clinical cancers show a range of levels of apoptosis following
treatment with anticancer agents. Further, the basic tenet that normal cells are
sensitive to apoptosis is also not true; indeed, the cells of many normal tissues do
not undergo apoptosis following DNA damage. In fact, there is considerable
evidence that the large variation in apoptosis between different tumor types is a
reflection of the sensitivity of induction of apoptosis in the normal cells from
which the tumors arose (3). Thus, inactivation of the apoptotic pathway during
tumorigenesis does not necessarily mean that the pathway is inactivated fol-
lowing DNA damage. Nonetheless, this does not invalidate the assumption that
the variation in apoptosis induction to anticancer therapy leads to the variation in
sensitivity of individual tumors to cancer therapy. We will examine the evidence
for this assumption in the following sections.
