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The goals of chemotherapy (and radiotherapy) are to eliminate tumor cell targets by
promoting cell death. In recent years, a major focus has been placed on programmed
cell death or apoptosis as the primary mechanism of cell killing. However, tumor
cells may respond to various forms of treatment in diverse ways, only some of which
culminate in cell death and loss of clonogenic survival. In addition to apoptosis, cell
death may occur through mitotic catastrophe, autophagy (a subtype of apoptosis), or
anoikis. Alternatively, cells may undergo either transient or prolonged growth arrest; in
addition, senescence arrest or accelerated senescence is now recognized as a response
to various treatments, which may also play a role in preventing cell transformation.
Consequently, “permanent” growth arrest, possibly mediated through senescence, could
contribute to loss of self-renewal capacity, particularly in solid tumors. The question
of why some tumor cells within a population ultimately recover proliferative capacity
(whether in cell culture, in xenograft models as a component of tumor growth delay,
or in patients in relation to disease recurrence) remains an unresolved question in
the fields of experimental chemotherapy and radiotherapy and a critical problem in
the clinical treatment of malignancies. The possibility that surviving and recovering
cells represent a resistant stem cell population has recently gained credence, although
evidence in support of this hypothesis is far from conclusive.
The purpose of this book is to contribute to an understanding of the growth arrest and
cell death pathways mediating the response to chemotherapy in tumor cells. The book
is divided into six sections. The first reviews the major cell death pathways. The second
develops the themes of telomeres, telomerase, and senescence in genetic stability and
tumorigenesis. The third provides an in-depth dissection of the critical DNA damage
and response signaling pathways. The fourth deals with the fundamental limitations
on therapy conferred by drug resistance, as well as current approaches to circumvent
or attenuate drug resistance. The fifth and sixth sections provide an analysis of our
understanding of the responses to both conventional strategies and newly developed
therapies against cancer.
It is our hope that this book will provide basic scientists and clinicians with a
deeper and more thorough understanding of the cellular responses of malignant cells to
common therapeutic modalities, which may determine the effectiveness of treatment,
both in the initial phase of the disease and the latter stages, including recurrence and
metastatic disease. |