Chapter 081. Principles of Cancer Treatment (Part 10) pdf

Chapter 081. Principles of
Cancer Treatment
(Part 10)

Integration of cell death responses. Cell death through an apoptotic
mechanism requires active participation of the cell. In response to interruption of
growth factor (GF) or propagation of certain cytokine death signals (e.g., tumor
necrosis factor receptor, TNF-R), there is activation of "upstream" cysteine
aspartyl proteases (caspases), which then directly digest cytoplasmic and nuclear
proteins, resulting in activation of "downstream" caspases; these cause activation
of nucleases, resulting in the characteristic DNA fragmentation that is a hallmark
of apoptosis. Chemotherapy agents that create lesions in DNA or alter mitotic
spindle function seem to activate aspects of this process by damage ultimately
conveyed to the mitochondria, perhaps by activating the transcription of genes
whose products can produce or modulate the toxicity of free radicals. In addition,
membrane damage with activation of sphingomyelinases results in the production
of ceramides that can have a direct action at mitochondria. The antiapoptotic
protein bcl2 attenuates mitochondrial toxicity, while proapoptotic gene products
such as bax antagonize the action of bcl2. Damaged mitochondria release
cytochrome C and apoptosis-activating factor (APAF), which can directly activate
caspase 9, resulting in propagation of a direct signal to other downstream caspases
through protease activation. Apoptosis-inducing factor (AIF) is also released from
the mitochondrion and then can translocate to the nucleus, bind to DNA, and
generate free radicals to further damage DNA. An additional proapoptotic
stimulus is the bad protein, which can heterodimerize with bcl2 gene family
members to antagonize apoptosis. Importantly, though, bad protein function can
be retarded by its sequestration as phospho-bad through the 14-3-3 adapter
proteins. The phosphorylation of bad is mediated by the action of the AKT kinase
in a way that defines how growth factors that activate this kinase can retard
apoptosis and promote cell survival.
Targeted agents differ from chemotherapy agents in that they do not

indiscriminately cause macromolecular lesions but regulate the action of particular
pathways. For example, the p210
bcr-abl
fusion protein tyrosine kinase drives chronic
myeloid leukemia (CML), and HER-2/neu stimulates the proliferation of certain
breast cancers. The tumor has been described as "addicted" to the function of these
molecules in the sense that without the pathway's continued action, the tumor cell
cannot survive. In this way, targeted agents may alter the "threshold" tumors have
for undergoing apoptosis without actually creating any molecular lesions such as
direct DNA strand breakage or altered membrane function.
While apoptotic mechanisms are important in regulating cellular
proliferation and the behavior of tumor cells in vitro, in vivo it is unclear whether
all of the actions of chemotherapeutic agents to cause cell death can be attributed
to apoptotic mechanisms. However, changes in molecules that regulate apoptosis
are correlated with clinical outcomes (e.g., bcl2 overexpression in certain
lymphomas conveys poor prognosis; pro-apoptotic bax expression is associated
with a better outcome after chemotherapy for ovarian carcinoma). A better
understanding of the relationship of cell death and cell survival mechanisms is
needed.
Resistance to chemotherapy drugs has been postulated to arise either from
cells not being in the appropriate phase of the cell cycle to allow drug lethality, or
from decreased uptake, increased efflux, metabolism of the drug, or alteration of
the target, e.g., by mutation or overexpression. Indeed, p170PGP (p170 P-
glycoprotein; mdr gene product) was recognized from experiments with cells
growing in tissue culture as mediating the efflux of chemotherapeutic agents in
resistant cells. Certain neoplasms, particularly hematopoietic tumors, have an
adverse prognosis if they express high levels of p170PGP, and modulation of this
protein's function has been attempted by a variety of strategies.
Chemotherapeutic agents where drugs acting by different mechanisms were
combined (e.g., an alkylating agent plus an antimetabolite plus a mitotic spindle

blocker) proved to be more effective than single agents. Particular combinations
were chosen to emphasize drugs whose individual toxicities to the host were, if
possible, distinct. As agents emerge with novel mechanisms of action,
combinations of drugs and targeted agents may maximize the chances of affecting
critical pathways in the tumor.
Chemotherapeutic Agents Used for Cancer Treatment
Table 81-2 lists commonly used cancer chemotherapy agents and pertinent
clinical aspects of their use. The drugs and schedules listed are examples that have
proved tolerable and useful; the specific doses that may be used in a particular
patient may vary somewhat with the particular treatment protocol, or plan, of
treatment. Significant variation from these dose ranges should be carefully verified
to avoid or anticipate toxicity. Not included in Table 81-2 are hormone receptor–
directed agents, as the side effects are generally those expected from the
interruption or augmentation of hormonal effect, and doses used in most cases are
those that adequately saturate the intended hormone receptor. The drugs listed may
be usefully grouped into three general categories: those affecting DNA, those
affecting microtubules, and molecularly targeted agents.