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Since its publication in 1950, the series "The Enzymes" has been established as an important reference book for researchers and students in the field of enzymology, biochemistry and biophysics and medical research. A number of scientists have served as a series editor for the Enzymes. Topics covered range from characterizations of various enzymes, biochemical processes and medical applications. This chapter provides an overview of the history of The Enzymes., (Copyright © 2023. Published by Elsevier Inc.)

Cancer is a worldwide problem afflicting 19 million people. Inhibition of DNA synthesis has been a cornerstone of anticancer therapy. A variety of chemotherapy drugs have been developed and many of these are aimed at inhibiting DNA synthesis, as they damage DNA, form DNA adduct and interfere with DNA synthesis. Another type of chemotherapy interferes with the synthesis of nucleotide pools. There are also other types of drugs that inhibit topoisomerases resulting in the interference with DNA replication and transcription. Significant progress has been made regarding radiation therapy that includes X-ray (and γ-ray), proton therapy and heavy ion therapy. The Auger therapy is a type of radiation therapy that differs from X-ray, proton or heavy ion therapy. The method relies on the use of high Z elements such as gadolinium, iodine, gold or silver. Irradiation of these elements results in the release of electrons including the Auger electrons that have strong DNA damaging effect. Tamanoi et al. developed novel nanoparticles containing gadolinium or iodine to place high Z elements at the periphery of the nucleus thus localizing them close to DNA. Irradiation with monochromatic X-ray resulted in the formation of double-strand DNA breaks leading to the destruction of tumor mass. Comparison of conventional X-ray therapy and the Auger therapy is discussed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

DNA is under a variety of assaults. As a result, different damages accumulate on DNA. These include base changes, single-strand breaks and double-strand breaks. In this volume and also briefly in the following volume, we discuss DNA damage and double-strand breaks. In particular, we focus on double-strand breaks. We discuss types of double-strand breaks as well as methods to detect them. We also discuss how DNA breaks are formed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Publication of the second edition of The Enzymes series was initiated in 1959 and eight volumes were published. This chapter describes volumes 1-3. All the eight volumes were edited by Paul D. Boyer, Henry Lardy and Karl Myerback. Authors and chapter titles are listed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Enzymes series was initiated in 1950 with the publication of a book entitled, "The Enzymes: Chemistry and Mechanism of Action" edited by James B. Sumner and Karl Myerback. There are two parts, Part 1 and Part 2 and the book contains 78 chapters. Authors and chapter titles for Part 1 and Part 2 are listed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Publication of the second edition of The Enzymes series was initiated in 1959 and eight volumes were published. This chapter describes volumes 4-8. All eight volumes were edited by Paul D. Boyer, Henry Lardy and Karl Myerback. Authors and chapter titles are listed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Irradiation of high Z elements such as iodine, gold, gadolinium with monochromatic X-rays causes photoelectric effects that include the release of Auger electrons. Decay of radioactive iodine such as I-123 and I-125 also results in multiple events and some involve the generation of Auger electrons. These electrons have low energy and travel only a short distance but have a strong effect on DNA damage including the generation of double-strand breaks. In this chapter, we focus on iodine and discuss various studies that used iodine-containing chemicals to generate Auger electrons and cause DNA double-strand breaks. First, DNA synthesis precursors containing iodine were used to place iodine on DNA. DNA binding dyes such as iodine Hoechst were investigated for Auger electron generation and DNA breaks. More recently, iodine containing nanoparticles were developed. We describe our study using tumor spheroids loaded with iodine nanoparticles and synchrotron-generated monochromatic X-rays. This study led to the demonstration that an optimum effect on DNA double-strand break formation is observed with a 33.2keV X-ray which is just above the K-edge energy of iodine., (Copyright © 2022 Elsevier Inc. All rights reserved.)

DNA damage and breaks are events that happen to DNA which exert a variety of influence on cell physiology including inhibition of DNA synthesis, repair response, cell cycle effect and cell death. Thus, it is important to deepened understanding of these events. In volume 51, we discussed topics including (1) assays to detect double-strand breaks, (2) conditions leading to double-strand breaks, (3) effects of irradiation, (4) DNA structure and chromatins, and (5) direct and indirect effect on DNA. Contributing authors and a table of contents for volume 51 are mentioned. We also discuss further issues and topics that need to be featured in future volumes. These include DNA damage sensors, DNA damage response proteins, and double-strand break repair pathways., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chick chorioallantoic membrane (CAM) assay provides a convenient and versatile model for the study of tumor formation, angiogenesis and metastasis. While the assay has been used for more than 100 years, the CAM assay has recently received renewed interest. One of the recent interests comes from the development of Precision Medicine in cancer therapy. The idea is to develop treatments that are tailor-made for each individual patient. For this to happen, patient-derived tumor models are critical and the CAM assay can make significant contribution. The other development concerns various applications of the CAM assay. Using this assay, various reagents have been identified. This includes sensitizers for radiation therapy and photodynamic therapy. We also discuss boron neutron capture therapy (BNCT) that is based on the splitting of boron-10 upon exposure to neutron beam. Recently, various boron-10 reagents have been developed and they can be examined for their efficacy for BNCT therapy using the CAM assay., (© 2019 Elsevier Inc. All rights reserved.)

Thiol-organosilica nanoparticles are a promising nanomaterial for biomedical applications. The enhanced permeability and retention (EPR) effect is useful for tumor targeting within the biomedical applications of nanomaterials, and nanomaterials with a size of less than 200 nm exhibit the maximum EPR effect. However, the synthesis of thiol-organosilica nanoparticles with a diameter of less than 200 nm is not efficient for the yield using the present conventional synthetic methods. Herein, we report the development of an efficient synthetic method of thiol-organosilica nanoparticles with a diameter of less than 200 nm using an anionic surfactant and discuss its mechanism. Compared with the conventional synthetic methods, a greater than 10-fold miniaturization of thiol-organosilica nanoparticles and an approximately 40-fold increase in the production efficiency of small thiol-organosilica nanoparticles were achieved using the sodium dodecyl sulfate (SDS)-addition synthetic method or sodium dodecylbenzenesulfonate (SDBS)-addition synthetic method. This is the first report about the miniaturization of organosilica nanoparticles induced by an anionic surfactant. The SDS-addition synthetic method or SDBS-addition synthetic method will accelerate the biomedical applications of thiol-organosilica nanoparticles., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Synthesis of mesoporous silica nanomaterials occurred in the late 1980s and early 1990s. Since then, we have seen dramatic increase in the number of publication dealing with this nanomaterial. In particular, there have been a large number of publications regarding biomedical application of mesoporous silica nanoparticles including their use in cancer therapy and diagnosis. Various surface modification strategies have been explored to enhance drug loading and to target them to tumor. In addition, the nanoparticles have been armed with controlled release capability. In this review, we point out some crucial issues regarding the material, which will be discussed in more detail in chapters of this volume., (© 2018 Elsevier Inc. All rights reserved.)

Biodegradable PMO (Periodic Mesoporous Organosilica) has emerged as a promising type of mesoporous silica based nanoparticles for clinical translation. We as well as others have synthesized and characterized three types of nanoparticles containing disulfide, tetrasulfide or peptide-like bonds within their framework. Biodegradable PMO has high drug loading efficiency and can be taken up into cancer cells. Our experiments utilizing the chicken egg tumor model uncovered excellent capability to accumulate and deliver anticancer drugs to the tumor. These results will be described and their significance will be discussed. The chicken egg tumor model provides a convenient and versatile model for characterizing nanoparticles., (© 2018 Elsevier Inc. All rights reserved.)

Mesoporous silica nanoparticles (MSNs) provide a promising vehicle for anticancer drug delivery. Various animal studies point to the efficacy of this nanoparticle for delivering anticancer agents (drug and siRNA) to inhibit tumor growth. These studies also showed tumor accumulation of MSN nanoparticles. While the extent of tumor accumulation differed, the study showed that it is possible to achieve significant accumulation of nanoparticles in the tumor. Biocompatibility and safety of MSN were also demonstrated by these studies., (© 2018 Elsevier Inc. All rights reserved.)

Alterations of enzyme activity or enzyme levels in cancer tissue have been documented over the years. Taking advantage of these observations, various strategies for drug activation and drug delivery have been developed. One example is a mechanism called "prodrugs" that generates active drugs by enzyme cleavage. Another example is enzyme-induced anticancer drug release mechanisms. This system is constructed by incorporating enzyme-sensitive linkages to materials such as hydrogels and nanodelivery vehicles, including liposomes, polymer micelles, and mesoporous silica nanoparticles. Various release mechanisms for anticancer drugs and siRNA have been developed. In addition, enzyme cleavage is utilized in nanodelivery vehicles that contain nanomachines. One example is nanovalve that can be opened by enzyme cleavage. Another example is enzyme-induced release of nanoparticles from multistage vehicles. Finally, colon-specific drug delivery by azoreductase cleavable mechanism is discussed., (© 2017 Elsevier Inc. All rights reserved.)

Phytochemicals are a powerful group of chemicals that are derived from natural resource, especially with plants origin. They have shown to exhibit chemoprevention and chemotherapeutic effects not only in cell lines and in animal models of cancer but also some of them are in the clinical trial phase I and II. Despite numerous reports of these phytochemical effects on cancer, an overview of the mechanisms of their action and their effects on various cellular and molecular functions important in the inhibition of cancer progression has been lacking. In this review, we attempt to catalogue various studies to examine the effect of phytochemicals in cancer initiation, promotion, signaling, and epigenetic changes. Because of the numerous studies in these topics, we only pointed out to some examples in each section., (© 2015 Elsevier Inc. All rights reserved.)

Saffron carotenoids, crocin and crocetin, have shown anticancer activity in various animal models of cancer and against different cancerous cell lines. The radical scavenging property and activation of antioxidant defense system are two well-known characteristics of these compounds. However, the results of the studies indicated other mechanisms could also be involved in this function. Insights into various molecular mechanisms of action for crocin and crocetin have been obtained in recent years. The results indicated that despite the structural similarity of crocin and crocetin, their anticancer effects may exert through different mechanisms. Particular interest concerns the ROS-dependent signaling pathways of crocetin. Saffron compounds are safe and may provide inexpensive therapy for treating cancer. They also have protective potential in targeting other disorders including diabetes, Alzheimer's and cardiovascular disease, cognitive deficits, ischemia-induced retinal damage, and many other diseases., (© 2014 Elsevier Inc. All rights reserved.)

Natural products and phytochemicals have extensively attracted for their various biological effects, especially for both treatment and prevention of cancer. In this book, we try to introduce various phytochemicals as cancer therapy targets with emphasize on their effect on signal transduction pathways and their molecular targets., (© 2014 Elsevier Inc. All rights reserved.)

K-Ras and N-Ras are mutated in a wide range of human cancers, thus making these proteins attractive targets of anticancer drug development. However, no effective compounds have been obtained so far. One of the approaches taken to inhibit the function of K-Ras and N-Ras is to interfere with their membrane association. Various attempts have been taken. In the first example, we examine the approach conceived in early 1990s to inhibit protein prenylation that is required for their membrane association. The initial premise that the inhibition of Ras farnesylation leads to the inhibition of Ras was not realized, mainly due to alternative prenylation of K-Ras and N-Ras proteins. This led to the idea that the combined inhibition of FTase and GGTase-I can block membrane association of K-Ras and N-Ras. Dual specificity inhibitors of FTase and GGTase-I (DPIs) were also developed. These compounds were tested in preclinical and clinical studies. It appears that sufficiently high concentration of the drug to inhibit K-Ras was not achieved in previous attempts. In addition, dose-limiting toxicity has been observed and this was primarily ascribed to GGTase-I inhibition. Strategies to confer cancer targeting capabilities to the inhibitors may overcome the dose-limiting toxicity. In the second approach, postprenylation events were exploited. This led to the development of various inhibitors including the ICMT inhibitors. Finally, recent identification of compounds that inhibit the interaction between K-Ras and PDE-δ is discussed., (© 2013 Elsevier Inc. All rights reserved.)

MCP compounds were developed with the idea to inhibit RAS/RAF interaction. They were identified by carrying out high-throughput screens of chemical compounds for their ability to inhibit RAS/RAF interaction in the yeast two-hybrid assay. A number of compounds including MCP1, MCP53, and MCP110 were identified as active compounds. Their inhibition of the RAS signaling was demonstrated by examining RAF and MEK activities, phosphorylation of ERK as well as characterizing their effects on events downstream of RAF. Direct evidence for the inhibition of RAS/RAF interaction was obtained by carrying out co-IP experiments. MCP compounds inhibit proliferation of a wide range of human cancer cell lines. Combination studies with other drugs showed that MCP compounds synergize with MAPK pathway inhibitors as well as with microtubule-targeting chemotherapeutics. In particular, a strong synergy with paclitaxel was observed. Efficacy to inhibit tumor formation was demonstrated using mouse xenograft models. Combination of MCP110 and paclitaxel was particularly effective in inhibiting tumor growth in a mouse xenograft model of colorectal carcinoma., (© 2013 Elsevier Inc. All rights reserved.)

The Ras superfamily G-proteins are monomeric proteins of approximately 21kDa that act as a molecular switch to regulate a variety of cellular processes. The structure of the Ras superfamily G-proteins, their regulators as well as posttranslational modification of these proteins leading to their membrane association have been elucidated. The Ras superfamily G-proteins interact at their effector domains with their downstream effectors via protein-protein interactions. Mutational activation or overexpression of the Ras superfamily G-proteins has been observed in a number of human cancer cases. Over the years, a variety of approaches to inhibit the Ras superfamily G-proteins have been developed. These different approaches are discussed in this volume., (© 2013 Elsevier Inc. All rights reserved.)

The TSC/Rheb/TORC1/S6K/S6 signaling pathway plays critical roles in regulating protein synthesis and growth in eukaryotes. Our recent work using fission yeast Schizosaccharomyces pombe revealed that this signaling pathway is conserved from humans to fission yeast. In addition to target of rapamycin (TOR) homologsand tuberous sclerosis complex (TSC) homologs, fission yeast but not budding yeast, has a functional homolog of Rheb, a small G-protein acting as an activator of TOR complex 1 (TORC1). Several lines of genetic evidence suggest that the Tsc1-Tsc2 complex and Rheb act as upstream players of TORC1 in fission yeast. We have recently demonstrated that TORC1, but not TORC2, regulates phosphorylation of ribosomal protein S6 in response to nutrient availability. Candidate S6 kinase (S6K) protein has been identified. In addition, we find that rapamycin prevents a subset of TORC1 activity to regulate S6 phosphorylation in fission yeast.

Rheb belongs to a unique family within the Ras superfamily of G-proteins. Although initially identified in rat brain, this G-protein is highly conserved from yeast to human. While only one Rheb is present in lower eukaryotes, two Rheb proteins exist in mammalian cells. A number of studies establish that one of the functions of Rheb is to activate mTOR leading to growth. In particular, the ability of Rheb to activate mTORC1 in vitro points to direct interaction of Rheb with the mTORC1 complex. Additional functions of Rheb that are independent of mTOR have also been suggested.

Rheb (Ras homolog enriched in brain) is a GTPase conserved from yeast to human and belongs to a unique family within the Ras superfamily of GTPases. Rheb plays critical roles in the activation of mTOR, a serine/threonine kinase that is involved in the activation of protein synthesis and growth. mTOR forms two distinct complexes, mTORC1 and mTORC2. While mTORC1 is implicated in the regulation of cell growth, proliferation, and cell size in response to amino acids and growth factors, mTORC2 is involved in actin organization. However, the mechanism of activation is not fully understood. Therefore, studies to elucidate the Rheb-mTOR signaling pathway are of great importance. Here we describe methods to characterize this pathway and to evaluate constitutive active mutants of Rheb and mTOR that we recently identified. Constitutive activity of the mutants can be demonstrated by the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) and eIF4E-binding protein 1 (4E-BP1) both in vivo and in vitro after starving cells for amino acids and growth factors. In addition, formation and activity of mTORC1 and mTORC2 can be measured by immunoprecipitating these complexes and carrying out in vitro kinase assays. We also describe a protocol for rapamycin treatment, which directly inhibits mTOR and can be used to investigate the mTOR signaling pathway in cell growth, cell size, etc.

The small, Ras-like GTPase Rheb plays an important role in the regulation of cell growth by the insulin/PI3K and nutrient/TOR pathways in eukaryotic systems. Studies in genetically tractable organisms such as Drosophila melanogaster and fission yeast (S. pombe) were critical for establishing the significance of Rheb in cell growth. In Drosophila, we find that overexpression of Drosophila Rheb (dRheb) in S2 cells causes their accumulation in S phase and an increase in cell size. In contrast, treatment of S2 cells with double-stranded RNA (RNAi) toward dRheb results in G1 arrest and a reduction in cell size. These altered cell size phenotypes observed in culture are also recapitulated in vivo. Overexpression of dRheb results in increased cell and tissue size without an increase in cell number; reduction of dRheb function results in reduced cell and tissue size. In S. pombe, inhibition of Rheb (SpRheb) expression also results in small, rounded cells that arrest in G0/G1. We will discuss here how we use Drosophila and S. pombe to explain a mechanism by which Rheb promotes cell growth.