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Control of programmed cell death in normal and leukemic cells: new
implications for therapy
L Sachs and J Lotem
Department of Molecular Genetics and Virology, Weizmann Institute of
Science, Rehovot, Israel.
Programmed cell death (apoptosis) is a normal process by which cells are
eliminated during normal embryonic development and in adult life.
Disruption of this normal process resulting in illegitimate cell survival
can cause developmental abnormalities and facilitate cancer development.
Normal cells require certain viability factors and undergo programmed cell
death when these factors are withdrawn. The viability factors are required
throughout the differentiation process from immature to mature cells.
Although many viability factors are also growth factors, viability and
growth are separately regulated. Viability factors can have clinical value
in decreasing the loss of normal cells including the loss that occurs after
irradiation, exposure to other cytotoxic agents or virus infection
including AIDS. There is no evidence that occurs after irradiation,
exposure to other cytotoxic agents or virus infection including AIDS. There
is no evidence that cancer cells are immortal. Programmed cell death can be
induced in leukemic cells by removal of viability factors, by cytotoxic
therapeutic agents, or by the tumor-suppressor gene wild-type p53. All
these forms of induction of programmed cell death in leukemic cells can be
suppressed by the same viability factors that suppress programmed cell
death in normal cells. A tumor-promoting phorbol ester can also suppress
this death program. The induction of programmed cell death can be enhanced
by deregulated expression of the gene c-myc and suppressed by the gene
bcl-2. Mutant p53 and bcl-2 suppress the enhancing effect on cell death of
deregulated c-myc, and thus allow induction of cell proliferation and
inhibition of differentiation which are other functions of deregulated
c-myc. The suppression of cell death by mutant p53 and bcl-2 increases the
probability of developing cancer. The suppression of programmed cell death
in cancer cells by viability factors suggests that decreasing the level of
these factors may increase the effectiveness of cytotoxic cancer therapy.
Treatments that downregulate the expression or activity of mutant p53 and
bcl-2 in cancer cells should also be useful for therapy.
Volume 82,
Issue 1,
pp. 15-21,
07/01/1993
Copyright © 1993 by The American Society of Hematology
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