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. . 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 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. resulting in activation of "downstream" caspases; these cause activation of nucleases, resulting in the characteristic DNA fragmentation that is a hallmark of apoptosis. Chemotherapy