Apoptotic Pathways as Targets for Novel Therapies in Cancer and Other Diseases , edited by M Los SB Gibson. Springer Science+Business Media Inc., New York, NY, USA, 2005, 395pp, $149, hardcover. ISBN 0-387-23384-9

As recently as three decades ago, the term ‘apoptosis’ was known to perhaps only a few dozen specialists worldwide. Moreover, even those who knew the actual meaning of this word could not imagine at that time that the pharmacologic or biologic manipulation of cell death will soon provide new hopeful opportunities for drug discovery and development. Nowadays, apoptosis-related subjects have turned out to be the topic of the day. Within just 1 year, we have witnessed the appearance of three books, Apoptosis in Health and Disease: Clinical and Therapeutic Aspects (by Holcik, LasCasse, MacKenzie, and Korneluk), Application of Apoptosis to Cancer Treatment (by Sluyser), and now Los and Gibson's work, all of them accurately reflecting the actual state of this mushroomed subject. The monograph by Los and Gibson is divided into 17 chapters that have been contributed by 46 authors from around the globe, many of whom are leading authorities in their respective fields. Although the book covers a broad spectrum of problems, the bulk of the volume is devoted totally or in part to the novel strategies of cancer treatment by regulation of apoptosis. In the remaining surveys, the authors highlight the progress that has been made in the development and application of apoptosis-targeting agents to treat a wide variety of noncancer diseases.

Two chapters in the book are of general tutorial value, namely ‘Apoptotic Pathways and Their Regulation’ by Brouckaert and co-authors, which gives basic principles of apoptotic machinery functioning and a chapter by Los and his co-authors thoroughly treating the current techniques used for identifying apoptosis. These chapters can be read with profit by nonspecialists who are curious to learn more about drugs that target disturbed apoptosis, but who have limited knowledge regarding molecular mechanisms of cell death and the methodology utilized in the field.

Brouckaert and co-authors discuss in-depth the caspase family of endopeptidases, which play a pivotal role in apoptotic cell dismantling. They also analyse other cell death signalling molecules, including the family of Bcl-2-like proteins. The current knowledge of the main players of cellular pathways suppressing apoptosis is briefly described, and then several alternative nonapoptotic modes of caspase-independent cell death are also considered.

The chapter by Los et al. contains detailed protocols for accurate detection, quantification and characterization of dying cells, including Western blotting, flow cytometry, ELISA, etc. All these contemporary techniques, together with the required equipment are described in lucid detail. Of particular interest is the application of the highly sensitive cytochrome c-based technique to monitor cytochrome c level (specific for apoptosis) in the serum of cancer patients under therapeutic intervention.

Besides the general aspects of apoptotic machinery and methodology of studying apoptosis, the various topics pertaining to specific aspects of applied apoptosis research are thoroughly regarded in the book. The mechanisms of anticancer drug action (Chapter II) and the components of extrinsic (death receptor) or intrinsic (mitochondrial) death pathways (Chapters III and V) are regarded as suitable objects for targeted therapy. The exploitation of survivin, XIAP, Smac, Omi, p53, and growth factor/growth factor receptor-signalling pathways as attractive targets for the development of anticancer agents is discussed in Chapters VI, VII, and VIII, respectively. Effective strategies developed to date include the use of monoclonal antibodies (MoAbs), recombinant proteins, peptides, small organic molecules, antisense oligonucleotides (AO), RNA interference (RNAi), and gene constructs. Preclinical or clinical studies presented in these surveys have demonstrated that many of these new compounds are capable of activating apoptosis selectively and effectively in malignant cells, without producing the severe side effects typical of conventional drugs. As for myself, the most interesting apoptosis-related pharmacological strategies of drugs designed for cancer treatment were those targeting protein refolding. It is encouraging that such a small molecule as, for example, PRIMA (for ‘p53 reactivation and induction of massive apoptosis’), can reactivate mutant p53-dependent transcription and apoptosis in vivo, suggesting the feasibility of this approach for reactivation of any other mutated proteins. The pharmacological inhibition of cell survival signalling has an enormous potential (see the chapter ‘Growth factors, receptors, and kinases: their exploration to target cancer’), although some disappointing results of clinical studies of kinase inhibitors in cancer patients are unfortunately omitted.

Novel therapeutics that selectively target the NF-kappaB gene or protein are critically analysed in the chapters ‘Nuclear transcription factor-κB: a drug target for all seasons’ by Garg and Aggarwal and ‘Targeting the proteasome in cancer therapy’ by Orlowsky. Especially useful at this point is the detailed information on the cellular pathways leading to NF-kappaB activation as well as its involvement in tumour promotion and cellular resistance to different treatments. It is interesting to learn that there are over 150 exogenous inhibitors of NF-kappaB, both natural and synthetic. The most potent among them is proteasome inhibitor PS-341 (now known as bortezomib), which has been already evaluated in a variety of trials including clinical studies in phase III setting. The discussion of the promising clinical results obtained for bortezomib, used both in haematologic malignancies and solid tumours, is thorough and concise, based on careful analyses and personal experiences. Nevertheless, the observation that knockout mice with a complete deficiency of NF-kappaB gene are subject to serious toxicity and prenatal death should also be taken into account. In this context, the author himself cautions: ‘It is clear that effective drug development targeting κB must focus on its partial and specific inhibition’ (p. 314).

The 11th and 13th chapters are, respectively, devoted to the therapeutic value of MoAbs and RNAi-based therapeutics, the subjects each of which alone could occupy a whole book. Besides the well-known strategies involving the therapeutic use of the MoAbs, Jung and colleagues describe rather new anticancer approaches based on bispecific antibodies with tumour X Fas specificity. The authors note that, in addition to specific induction of apoptosis in tumour cells, the therapeutic benefit of these antibodies may be realized via the inhibition of tumour angiogenesis. However, I have not found strong evidence in the body of their text, which actually supports that assumption. Lin and Ying describe in detail their own vector-based D-RNAi (cDNA-mRNA hybrid interference) strategy and D-RNAi-derived micro-RNA agents developed for therapeutic purposes. The opportunities and the prospects for killing tumour cells by silencing apoptosis-related genes or inactivating HIV-infected cells using D-RNAi-based therapeutics are also discussed.

The book ends with two chapters that revolve around the problem of minimizing chemotherapy-related undesirable side effects. The chapter ‘Current strategies in tumour targeting’ by Mier and others focuses on the reduction of systemic toxicity of chemotherapeutics at the expense of tumour-specific drug delivery (or release from prodrugs). Alternatively, Blagosklonny and Darzynkiewicz consider therapeutic strategy based on consecutive use of cytostatic drugs to arrest normal cells and to reactivate apoptosis in malignant ones, and also chemotherapeutic agents selectively killing neoplastic cells. In addition, the novel promising approaches relying on rational drug combinations, including sensitizers to conventional chemo- and radiotherapy, are mentioned in other sections of the volume (Chapters II, III, V–VIII, and XI–XIV). Whether these drug combinations will result in more effective treatment of cancer patients remains to be seen in the forthcoming clinical investigations.

The remainder of the book concentrates on the numerous aspects pertaining to combating noncancer disorders and injury states. Caspases are discussed as valuable targets for drug development in a chapter presented by Knight and Hawkins. A number of promising peptide-based, peptidomimetic, and nonpeptidic caspase inhibitors are in focus here. Main indications for these drug candidates, such as acute or chronic diseases of the liver, the heart, and the nervous system, as well as autoimmune and infection diseases, are analysed in detail. Two of them, VX-740 and IDUN-6556, developed by Vertex Pharmaceuticals Inc. and Idun Pharmaceuticals Inc., now enter the early stages of clinical trials. Arguing for the benefits of anticaspase therapies, one should bear in mind that the major aim of such a treatment consists in not only preventing apoptosis but also in preserving the functions of the diseased cells.

Chapters by Ghivizzani, Gouze, and Gouze, and by Love present striking targets for apoptotic intervention in rheumatoid arthritis and stroke, respectively. In a former chapter, diverse strategies to eliminate specifically autoreactive cell populations are disclosed, including induction of apoptosis following intra-articular delivery of appropriate MoAbs and viral vectors. In stroke, inhibitors of caspases, calpains, CDK, JNK, p53, anti-JNK AO, as well as viral vectors that overexpress Bcl-2, represent new treatment modalities, which allow for a reduction of apoptotic neuronal death and have already shown promising results in preclinical testing. These innovative treatment approaches seem to be especially useful to be discussed in the context of existing anti-inflammatory therapies.

An advantage of the book is its appendix, which includes a comprehensive and detailed summary table of the new therapeutic agents designed to treat various diseases and injury states (14pp.). About 80 different drug-like molecules targeting death pathways are listed.

The index that follows the experimental-drug summary table, incorporating over 300 listings, allows for fast, table of content-independent, searching for experimental drugs, not only by their names but also by industry developmental codes. It also lists clinical conditions, thus allowing an easy association of an experimental treatment with a particular disease.

To me, it is unfortunate that the monograph provides no more than scanty information on the potential for utilizing apoptosis-regulated genes and proteins as prognostic and/or predictive markers in spite of hundreds of clinical cancer research trials on this important and rapidly growing subject. It is also regrettable that existing noninvasive technologies for in vivo visualization of apoptotic cells (such as single photon emission computerized tomography, positron emission tomography, or magnetic resonance imaging) have absolutely escaped the author's attention. Finally, the lack of the list of contributors is a disadvantage of the book design.

I think also that in future editions of the book in the sections dealing with the methodical aspects of cell death quantification, the recent recommendations of the Nomenclature Committee on Cell Death (see Cell Death Differ, 2005; 12: 1463–1467) encouraging the authors to avoid the expressions such as ‘percentage apoptosis’ and ‘replacing them by more precise description of the parameters that are actually measured’ should be taken into account.

Setting these criticisms apart, this is a well-edited, thoroughly referenced, comprehensive compendium that overviews almost all present and potential future treatments for many human diseases with application of novel drugs targeting death pathways.