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. ...
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Chapter 081. Principles of Cancer Treatment (Part 10) Chapter 081. Principles of Cancer Treatment (Part 10) Integration of cell death responses. Cell death through an apoptoticmechanism requires active participation of the cell. In response to interruption ofgrowth factor (GF) or propagation of certain cytokine death signals (e.g., tumornecrosis factor receptor, TNF-R), there is activation of upstream cysteineaspartyl proteases (caspases), which then directly digest cytoplasmic and nuclearproteins, resulting in activation of downstream caspases; these cause activationof nucleases, resulting in the characteristic DNA fragmentation that is a hallmarkof apoptosis. Chemotherapy agents that create lesions in DNA or alter mitoticspindle function seem to activate aspects of this process by damage ultimatelyconveyed to the mitochondria, perhaps by activating the transcription of geneswhose products can produce or modulate the toxicity of free radicals. In addition,membrane damage with activation of sphingomyelinases results in the productionof ceramides that can have a direct action at mitochondria. The antiapoptoticprotein bcl2 attenuates mitochondrial toxicity, while proapoptotic gene productssuch as bax antagonize the action of bcl2. Damaged mitochondria releasecytochrome C and apoptosis-activating factor (APAF), which can directly activatecaspase 9, resulting in propagation of a direct signal to other downstream caspasesthrough protease activation. Apoptosis-inducing factor (AIF) is also released fromthe mitochondrion and then can translocate to the nucleus, bind to DNA, andgenerate free radicals to further damage DNA. An additional proapoptoticstimulus is the bad protein, which can heterodimerize with bcl2 gene familymembers to antagonize apoptosis. Importantly, though, bad protein function canbe retarded by its sequestration as phospho-bad through the 14-3-3 adapterproteins. The phosphorylation of bad is mediated by the action of the AKT kinasein a way that defines how growth factors that activate this kinase can retardapoptosis and promote cell survival. Targeted agents differ from chemotherapy agents in that they do notindiscriminately cause macromolecular lesions but regulate the action of particularpathways. For example, the p210bcr-abl fusion protein tyrosine kinase drives chronicmyeloid leukemia (CML), and HER-2/neu stimulates the proliferation of certainbreast cancers. The tumor has been described as addicted to the function of thesemolecules in the sense that without the pathways continued action, the tumor cellcannot survive. In this way, targeted agents may alter the threshold tumors havefor undergoing apoptosis without actually creating any molecular lesions such asdirect DNA strand breakage or altered membrane function. While apoptotic mechanisms are important in regulating cellularproliferation and the behavior of tumor cells in vitro, in vivo it is unclear whetherall of the actions of chemotherapeutic agents to cause cell death can be attributedto apoptotic mechanisms. However, changes in molecules that regulate apoptosisare correlated with clinical outcomes (e.g., bcl2 overexpression in certainlymphomas conveys poor prognosis; pro-apoptotic bax expression is associatedwith a better outcome after chemotherapy for ovarian carcinoma). A betterunderstanding of the relationship of cell death and cell survival mechanisms isneeded. Resistance to chemotherapy drugs has been postulated to arise either fromcells not being in the appropriate phase of the cell cycle to allow drug lethality, orfrom decreased uptake, increased efflux, metabolism of the drug, or alteration ofthe target, e.g., by mutation or overexpression. Indeed, p170PGP (p170 P-glycoprotein; mdr gene product) was recognized from experiments with cellsgrowing in tissue culture as mediating the efflux of chemotherapeutic agents inresistant cells. Certain neoplasms, particularly hematopoietic tumors, have anadverse prognosis if they express high levels of p170PGP, and modulation of thisproteins function has been attempted by a variety of strategies. Chemotherapeutic agents where drugs acting by different mechanisms werecombined (e.g., an alkylating agent plus an antimetabolite plus a mitotic spindleblocker) proved to be more effective than single agents. Particular combinationswere chosen to emphasize drugs whose individual toxicities to the host were, ifpossible, distinct. As agents emerge with novel mechanisms of action,combinations of drugs and targeted agents may maximize the chances of affectingcritical pathways in the tumor. Chemotherapeutic Agents Used for Cancer Treatment Table 81-2 lists commonly used cancer chemotherapy agents and pertinentclinical aspects of th ...