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Recent evidence indicates that anti-apoptotic functions of BcI-2 can be regulated by its phosphorylation. According to the 'mitotic arrest-induced' model, multi-site phosphorylation of the BcI-2 loop domain is followed by cell death. In contrast, in cytokine-dependent cell lines, cytokines mediate phosphorylation of BcI-2 on S70, preventing apoptosis. As discussed in this review, these models are not mutually exclusive but reflect different cellular contexts. During mitotic arrest, signal transduction is unique and is fundamentally different from classical mitogenic signaling, since the nucleus membrane is dissolved, gene expression is reduced, and numerous kinases and regulatory proteins are hyperphosphorylated. Hyperphosphorylation of BcI-2 mediated by paclitaxel and other microtubule-active drugs is strictly dependent on targeting microtubules that in turn cause mitotic arrest. In addition to serine-70 (S70), microtubule-active agents promote phosphorylation of S87 and threonine-69 (T69), inactivating BcI-2. A major obstacle for identification of the mitotic BcI-2 kinase(s) is that inhibition of putative kinase(s) by any means (dominant-negative mutants, antisense oligonucleotides, pharmacological agents) may arrest cycle, preventing mitosis and BcI-2 phosphorylation. The role of BcI-2 phosphorylation in cell death is discussed.

Though the term apoptosis was originated in pathology and developmental biology as an alternative to necrosis, the tissue necrosis with inflammation is irrelevant to cell culture conditions where apoptosis is mostly studied. Furthermore, no one single morphological feature is either necessary or sufficient to define apoptosis. The emerging biochemical definition, a cell death with caspase activation, allows the distinction of alternative forms of cell death. Thus, inhibition of caspases delays but does not prevent cell death. Slow cell death without caspase activation may nevertheless be associated with DNA fragmentation. Oncogenic Ras, Raf, and mitogen-activated kinases inhibit apoptosis by affecting the cytochrome C/caspase-9 pathway but may arrest growth and cause slow cell death with delayed DNA fragmentation. Such 'slow' cell death without caspase activation is often caused by chemotherapeutic drugs. Whether a cell will undergo apoptosis or slow death depends not only on a chemotherapeutic agent but also on the readiness of cellular caspases. Therefore, one can distinguish apoptosis-prone (eg leukemia) vs apoptosis-resistant cells. Cell susceptibilities to spontaneous, starvation-induced and drug-induced apoptosis are correlated and characterize an apoptosis-prone phenotype. Finally, distinction of slow cell death allows rephrasing of a question regarding the goal of cancer therapy: apoptosis vs slow cell death, or cancer cell-selectivity regardless of the mode of cell death.

The possibility of inhibiting gene expression with antisense oligonucleotides (AS ODNs) in combination with more conventional chemotherapy is a very attractive modality in oncology. However, possible interaction between the ODN and drug must be considered. Here we show that ODNs protect cells from the cytostatic/cytotoxic action of actinomycin D (AMD), adriamycin, daunomycin or quinacrine, but not mitomycin, camptothecin, vincristine, cisplatin, etoposide (VP-16) or cycloheximide. The cytoprotective effect depends on ODN length as well as ability to interact directly with the cytotoxic drug and is only slightly sequence selective.

Seemingly disappointing, the Bcr-Abl kinase inhibitor STI-571 shares an 'unfortunate' characteristic with conventional cancer drugs: the development of drug resistance. I argue that the resistance must develop even faster to STI-571 than to conventional drugs, because STI-571 is so effective. This is predictable, but is it inevitable? And how do mechanisms of resistance in relapse depend on a degree of remission. In addition to mutation rate and number of tumor cells, one additional factor determines relapse vs. 'extinction' of the leukemia cell population.

Geldanamycin (GA), herbimycin A and radicicol bind heat-shock protein-90 (Hsp90) and destabilize its client proteins including v-Src, Bcr-Abl, Raf-1, ErbB2, some growth factor receptors and steroid receptors. Thus, Hsp90-active agents induce ubiquitination and proteasomal degradation of numerous oncoproteins. Depending on the cellular context, HSP90-active agents cause growth arrest, differentiation and apoptosis, or can prevent apoptosis. HSP-active agents are undergoing clinical trials. Like targets of most chemotherapeutics, Hsp90 is not a cancer-specific protein. By attacking a nonspecific target, HSP-90-active compounds still may preferentially kill certain tumor cells. How can this be achieved? How can therapeutic potentials be exploited? This article starts the discussion.

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ?accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. "Regulated cell death" (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death Fil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina Fil: Nomenclature Committee on Cell Death. Equipe 11 Apoptose, Cancer et Immunité. Centre de Recherche des Cordeliers; Francia