Frontiers in Anti-Cancer Drug Discovery

Ribonucleotide Reductase (RNR) plays a critical role in DNA synthesis, and is a well-recognized target for cancer chemotherapeutic and antiviral agents. RNR inhibition precludes DNA transcription and repair, from which results cell apoptosis. Many regulation checkpoints concerning RNR activity have been unravelled through the last two decades, with potential use to inhibit enzyme activity. This was accomplished by researchers from different but complementary areas from which several and different inhibitors have resulted. The volume of these studies has generated over 4000 articles since the discovery of RNR in 1960. Some of these compounds have already been approved by FDA and EMEA for the treatment of specific types of cancer, as it is the case of gemcitabine, fluoromethylene and hydroxyurea.

This review summarizes patents and papers during the period 1958 - 2009 dealing with the present understanding of ribonucleotide reductase biochemistry, mechanism of action and the most relevant data concerning RNR inhibition. Special attention is given to the inhibitors that have been patented and are currently in clinical use.

Thymidine phosphorylase (TP), also known as platelet derived endothelial cell growth factor (PD-ECGF), is an enzyme involved in thymidine synthesis and degradation and exerts an angiogenic activity. On the other hand, N4 – pentyloxycarbonyl-5'-deoxy-5-fluorocytidine, commonly called capecitabine (CAP), is a thymidine phosphorylase (TP) activated oral fluorpyrimidine, which generates 5-fluorouracil (5-FU) within tumors. In addition to this classical antitumor activity, recent studies suggest that CAP may act as an antiangiogenetic molecule. In this way the assessment of tumor microvessel density (MVD) in terms of endothelial cells positive to TP may identify the most vascularized tumor sensitive to CAP. This review article will summarize: (i) the biochemical activity of tissue expression of TP; (ii) the pharmacological profile of CAP as an anticancer compound and the central role of TP in its activation; (iii) the potential antiangiogenetic role of TP- activated CAP in tumors.

Breast cancer is the most common malignancy afflicting Western women today and causes many deaths due to metastatic disease. Upregulation of the plasminogen-activation system (PAS) strongly correlates with poor prognosis in metastatic breast cancer and targeting this system is a promising strategy for developing prophylactic anti-metastasis drugs. Two classes of PAS-targeting agents are inhibitors of the serine protease activity of urokinase plasminogen activator (uPA) and antagonists of the interaction of uPA with its cell surface receptor (uPAR). This review provides an overview of the role of PAS in cancer metastasis before discussing the small molecules and peptides from the patent literature since 2000 that target either uPA or uPA/uPAR interactions for use as anti-metastasis drugs.

Epigenetics as well as post-translational modifications of proteins are emerging as attractive novel targets for anti-cancer therapy. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two classes of enzymes that regulate histone acetylation, and altered activity of these enzymes has been identified in several cancers. An imbalance in histone acetylation can lead to changes in chromatin structure and transcriptional dysregulation of genes that are involved in the control of proliferation, cell-cycle progression, differentiation and/or apoptosis. In addition, several non-histone protein substrates, such as transcription factors, chaperone proteins or tubulin, undergo acetylation as a key post-translational modification that regulates their half-lives and function. Several inhibitors of HDACs have recently been shown to induce growth arrest and apoptosis in a variety of human cancer cells and have been patented as anticancer agents. Although several clinical studies with HDAC inhibitors (HDAC-Is) are ongoing, the molecular basis for their tumor selectivity remains unknown, thereby presenting a challenge for the cancer research community.

The first line therapy for chronic myeloid leukemia (CML) was dramatically altered within a few years of the introduction of Abl specific tyrosine kinase inhibitor, imatinib mesylate to the clinic. However, refractoriness and early relapse have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib mesylate binding are most critical cause of imatinib resistance. To override resistance, four second generation ATP competitive Abl kinase inhibitors such as dasatinib, nilotinib, bosutnib and bafetinib have been developed. Although these inhibitors can inhibit the phosphorylation of most mutated Bcr-Abl, none of these are effective for T315I. Thus, Bcr-Abl/T315I is an important and challenging target for discovery of CML therapeutics. Novel agents such as ATP noncompetitive Abl kinase inhibitors and multikinase inhibitors including Aurora kinase which can inhibit the phosphorylation of Bcr-Abl/T315I have been developed. This review is focused on the novel compounds which claim the efficacy against Bcr-Abl/T315I.

Aurora kinases (AK) are the name given to a family of Serine/threonine (Ser/Thr) protein kinases. These proteins represent a novel family of kinases crucial for cell cycle control. The cell division process is one of the hallmarks of every living organism. Within the complete cell-cycle process, mitosis constitutes one of the most critical steps. The main purpose of mitosis is to segregate sister chromatics into two daughters cells. It is a complex biologic process, and errors in this mechanism can lead to genomic instability, a condition associated with tumorigenesis. This process is tightly regulated by several proteins, some of them acting as check-points that ultimately ensure the correct temporal and spatial coordination of this critical biologic process. Among this network of mitotic regulators, AK play a critical role in cellular division by controlling chromatid segregation. Three AK family members have been identified in mammalian cells: A, B, and C. These proteins are implicated in several vital events in mitosis. In experimental models, overexpression of AK can induce spindle defects, chromosome mis-segregation, and malignant transformation. Conversely, downregulation of AK expression causes mitotic arrest and apoptosis in tumor cell lines. The expression levels of human AK are increased in certain types of cancer including breast, colon, pancreatic, ovarian, and gastric tumors. This observation has lent an interest to this family of kinases as potential drug targets for development of new anticancer therapies. This review focuses in recent progress in the role of AK in tumorogenesis and the development of new anticancer drug against AK proteins. This manuscript includes some relevant patents as well.

Breast cancer management has become increasingly complex, requiring the integration of data not only from the patient's history and imaging modalities but also from specific tumor biomarkers and gene expression. Targeted and biologic therapies in breast cancer continue to evolve rapidly. The field of molecular targeted therapy has emerged. Its ultimate goal is to personalize and simplify treatment as well as minimize toxicity. This review aims at highlighting the current state-of-the-art in novel molecular targeted therapies for breast cancer based on multi-targeted small molecule tyrosine kinase inhibitors (TKI). The first two agents in this group entering clinic, Lapatinib (GW572016; Tykerb®) and SUNITINIB (SU11248; Sutent®) are discussed. This review article also includes relevant patents.

Melanoma is a significant, worldwide growing public health burden. Single-agent chemotherapy or immunotherapy remains the treatment of election for this disease when systemic therapy is offered. Malignant melanoma of the skin is distinguished by its capability to early metastatic spread by means of lymphatic vessels to regional lymph nodes. Herein new accomplishments on the role of lymphangiogenesis and of angiogenesis in cutaneous melanoma will be discussed, together with the possible application of these discoveries in developing prognostic and therapeutic tools in melanoma metastasis. Furthermore, the present review will summarize the main angiogenic inhibitors reported in the recent patents, with special emphasis on the aspects which have important implications for the prognosis and the treatment of human melanomas.

Angiogenesis, the formation of new blood vessels from preexisting microvasculature is a highly regulated process. Angiogenesis is controlled by both positive and negative factors thus providing several targets for drug discovery. Targeting tumor endothelial cells has gained much attention with the notion that tumors can be starved to death by cutting the lifeline of tumor cells, i.e. vascular endothelial cells. In this regard, the inhibition of angiogenesis represents a new approach to cancer therapy and several agents and approaches are in different stages of clinical development. These inhibitors were recently shown to constitute a new modality for cancer treatment. In this article, we will review the recent angiogenesis inhibitors-related patent literature. This review will cover specifically the discovery and development disclosures of endogenous inhibitors. The scope of this review is to give the reader a well structured patent literature review of these agents targeting different steps of the angiogenic process. Finally, we have summarized the key attributes of the emerging endogenous angiogenesis inhibitors that make them potent antitumor agents.

Proliferation, motility and differentiation of vascular endothelial cells (ECs) are critical steps in angiogenesis and are strictly controlled by different extracellular signals. Among mitogens, peptides binding to tyrosine kinase receptors (i.e. VEGFs and FGFs) are well known and are released by several cell types, including ECs and tumor cells. The binding of mitogens to their specific receptors triggers intracellular signalling cascades, involving a number of messengers working in a sort of network. In particular, in this review we describe the increases of calcium levels in the cytosol, a universal, evolutionary conserved and highly versatile signal involved in the regulation of EC's proliferation and motility.

Most mitogens generate cytosolic calcium rises through two mechanisms: entry from extracellular medium, through the opening of calcium permeable channels in the plasmamembrane, and release from intracellular organelles (mainly endoplasmic reticulum, ER).

Calcium entry, the main topic of this review, can be dependent on previously IP3- activated emptying of calcium stores (store-dependent or capacitative calcium entry - CCE), or independent on it (non capacitative calcium entry, NCCE). The intracellular pathways underlying calcium entry are under investigation and recently arachidonic acid (AA) and nitric oxide (NO) metabolism have been suggested to play a key role, at least in some cell types. Even if some calcium entry blockers are under clinical trial with encouraging results, a better knowledge about the molecular nature of calcium channels and their intracellular regulation, together with a more detailed description of spatiotemporal dynamics of intracellular calcium events, could lead to new and more specific strategies in therapeutical approach to cancer progression and angiogenesis.

Recently, the search for more effective and safer antineoplastic agents has led to synthesis and introduction into preclinical and clinical studies of a few new purine nucleoside analogues (PNA). Three of them: clofarabine (CAFdA), nelarabine, and forodesine (immucillin H, BCX-1777), despite belonging to the same group of drugs such as PNA, have shown some differences concerning their active forms, metabolic properties and mechanism of action. However, all these drugs have demonstrated promising activity in patients with relapsed and refractory acute lymphoblastic leukemia (ALL). CAFdA was approved for the therapy of relapsed or refractory ALL in the third line of treatment. It has proved promising in pediatric patients as well as in some patients who are able to proceed to allogenic hematopietic stem cell transplantation (HSCT). Moreover, the drug exhibits an efficacy in acute myeloid leukemia (AML), blast crisis of chronic myelogenous leukemia (CML-BP) and myelodysplastic syndrome (MDS). Nelarabine is recommended for T-ALL and T-cell lymphoblastic lymphoma (TLBL) with the overall response rates ranging from 11 to 60%. However, the use of the drug is limited by potentially severe neurotoxicity. Forodesine is a purine nucleoside phosphorylase (PNP) inhibitor and it has shown activity in relapsed and refractory T- and B-cells leukemias as well as in cutaneous T-cell lymphoma (CTCL). Recently patented, a few of inventions in the field of pharmaceutical preparation of new PNA have also been published. Great hopes are currently set on the use of these drugs in the treatment of lymphoid and myeloid malignancies in adult and in pediatric patients, however ongoing studies will help to define their role in the standard therapy.

Somatostatin (SS) was originally discovered as a hypothalamic neurohormone which inhibits growth hormone secretion. The synthesis of the first two metabolically stabilized and more potent SS analogs, octreotide and lanreotide leads to the establishment of applications for them and to introduction into routine therapies.

The effectiveness of octreotide or lanreotide in controlling symptoms and GH/IGFI hypersecretion in acromegalic patients, both preoperatively and postoperatively is well proven. Similarly, these drugs are also very effective in the treatment of TSHsecreting adenomas.

The introduction of these drugs into therapy of the functional neuroendocrine tumors of the gastrointestinal tract was a crucial step in the treatment. Octreotide and lanreotide are the drugs of choice in the treatment of patients with: VIPoma, glucagonoma and carcinoid syndrome. Somatostatin receptor scintigraphy with OctreoScan has been recommended as the best imaging technique in these tumors in the localization and staging procedure.

SS analogs, coupled to radioisotope or cytotoxic drugs, create another class of SS molecules, very promising in the therapy of the endocrine glands tumors and in other tumors. Another class of SS analogs comprises hybrid molecules, which are chimera of sst2 agonist and D2 agonist, possessing more potent activity than these agonists, applied together.

Bortezomib represents the first proteasome inhibitor to have shown antitumour activity in both solid and haematological malignancies. Inhibition of the proteasome degradation machinery will result in increased apoptosis, decreased cell proliferation and reduced angiogenic cytokine production. Multiple myeloma is the prototype of cancer where bortezomib has shown marked in vitro and in vivo activity, which was followed by rapid translation to phase I, II and III clinical trials, and resulted in accelerated approval by the FDA for the treatment of patients with relapsed refractory disease, and later in newly diagnosed multiple myeloma patients. Subsequently, Bortezomib has been used in different clinical trials in other haematologic and solid tumours. This review focuses on the proteasome inhibition exerted by bortezomib, the first proteasome inhibitor to have shown anti-cancer activity in both solid and haematologic malignancies.

Dimerization of epidermal growth factor receptor (EGFR) on the cell membrane of tumor cells has been implicated in triggering a complex signal cascade that leads to increased tumor proliferation and survival. Cetuximab is a human-murine chimeric monoclonal antibody designed to target EGFR and competitively inhibit dimerization by circulating ligands. By this mechanism, it works to prevent this signal cascade thus hindering tumor proliferation. Cetuximab has been shown in a randomized phase III clinical trial to significantly increase overall survival when it is added to radiation therapy in the treatment of locally advanced squamous cell carcinoma of the head and neck. In this manuscript, the mechanism of cetuximab with its associated patents is reviewed, with its role with chemotherapy and radiation in the management of head and neck cancer along with future directions of this targeted cancer therapy.

The development of metal complexes as antitumor agents has attracted much attention in recent years. Platinum complexes afford an opportunity for the discovery of new antitumor drugs with truly novel mechanisms of action. The dose-limiting severe toxic side-effects of platinum-based chemotherapy, the problem of inherent or therapy-induced resistance, the limited activity in a range of tumors, and the meager tumor selectivity are the motivation for tremendous efforts and inventions in the development of novel anticancer platinum drugs. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on platinum coordination complexes as related to their anticancer properties. Beyond doubt, a deep understanding of the mechanisms of existing metal anticancer agents will build the basis for the rational design. With the aid of inorganic or coordination chemistry, it is possible to design novel therapeutic and diagnostic agents.

The c-Myc oncoprotein is a master regulator of genes involved in diverse cellular processes. Situated upstream of signalling pathways regulating cellular replication/growth as well as apoptosis/growth arrest, c-Myc may help integrate processes determining cell numbers and tissue size in physiology and disease. In cancer, this ‘dual potential’ allows cMyc to act as its own tumour suppressor. Evidently, given that deregulated expression of c-myc is present in most, if not all, human cancers (Table 1) and is associated with a poor prognosis, by implication these in-built ‘failsafe’ mechanisms have been overcome.

To explore the complex activity of c-Myc and its potential as a therapeutic target ‘post-genome era’ technologies for determining global gene expression alongside advanced new models for the study of tumourigenesis in vivo have proved invaluable. Thus, many recent studies have provided encouragement for the therapeutic targeting of c-Myc in cancer and have revealed new protein targets for manipulating aspects of c-Myc activity. The remarkable regression of even advanced and genetically unstable tumours, seen following deactivation of c-Myc in various models is particularly exciting.

This review will discuss what is known about the role of c-Myc in growth deregulation and cancer and will conclude with a discussion of the most promising recent developments in c-Myc-targeted therapeutics.

Vascular disrupting agents (VDAs) are a new class of potential anticancer drugs that selectively destroy tumor vasculature and shutdown blood supply to solid tumors, causing extensive tumor cell necrosis. VDAs target established tumor blood vessels, which are distinct from antiangiogenic agents that prevent the formation of new blood vessels. There are two types of VDAs, small molecules and ligand-directed agents. Most of the small molecule VDAs are tubulin inhibitors, including CA4P, ZD6126, AVE8062, OXi-4503, NPI-2358, MN-029, EPC2407, CYT997, MPC-6827, ABT-751 and TZT-1027. The others are synthetic flavonoids including FAA and DMXAA that induce the production of local cytokines such as TNF-alpha. VDAs have shown good antitumor efficacy in animal models, especially in combination with established anticancer agents. Several VDAs, including CA4P and DMXAA, have demonstrated good safety profile as well as some promising efficacy in phase I and II clinical trials. Currently CA4P, DMXAA and AVE8062 are in phase III clinical trials, NPI-2358, CYT997, MPC-6827 and ABT-751 are in phase II clinical trials, and OXi-4503 and EPC2407 are in phase I clinical trials. This review will focus on recent progress in the discovery and development of small molecule VDAs, including recently published patent applications and issued patents related with small molecule VDAs.

Gastrointestinal stromal tumors (GISTs) comprise a recently defined entity of the most common mesenchymal neoplasms of the gastrointestinal tract. Advances in the understanding of the molecular mechanisms of GIST pathogenesis have resulted in the development of a treatment approach which has become a model of targeted therapy in oncology. The introduction of imatinib mesylate (inhibiting KIT/PDGFRA (platelet-derived growth factor receptor-α) and their downstream signaling cascade) has revolutionized the therapy of advanced (inoperable and/or metastatic) GISTs. Imatinib has now become the standard of care in the treatment of patients with advanced GIST. However, a majority of patients eventually develop clinical resistance to imatinib. Over the last few years major progress has been made in elucidating the mechanism of disease progression (as secondary mutations in KIT and/or PDGFRA kinase domains) and resistance to imatinib. Currently, the sole approved second-line drug is sunitinib - a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET). However, a number of new generation tyrosine kinase inhibitors, alone or in combination, are being evaluated at present alongside treatment options alternative to inhibiting the KIT signaling pathway (as heat shock protein 90, insulin-like growth factor 1 receptor or mammalian target of rapamycin). This article discusses the factors relating to imatinib resistance as well as upcoming potentially effective treatment options for patients with progressive disease available in 2009 and those under investigation with more individualized treatment methods, which has been recently patented. This review focuses on the current achievements in targeted therapy of advanced GISTs, and how the insight into the resistance mechanisms may allow in the near future to treat patients with advanced GISTs.

E1A is a multifunctional adenoviral protein expressed early after infection that interferes with numerous important regulatory processes by interaction with host cell proteins or direct transcriptional activation of target genes. Although, initially identified as the adenoviral component that can cause malignant conversion of rodent cells, remarkable tumorsuppressive effects of E1A on various types of human cancer cells were observed. Gene therapeutic approaches with E1A are currently evaluated in animal models and early clinical studies. Therapeutic applications of E1A are covered by a series of patents which include the description of small variants (mini-E1A) that can be used for tumor suppression and E1A gene transfer in combination with conventional chemotherapy. In this mini review, we provide an introduction to E1A functions, summarize relevant patents, and discuss potential clinical applications of E1A gene transfer on basis of recent results of clinical and preclinical investigations.

Celecoxib (Celebrex, Pfizer, NY, USA) is a worldwide top branded COX-2-specific inhibitor. It was shown to provide relief of arthritic pain and inflammation and has recently been under investigation for the prevention and treatment of cancer. However, recent studies showed that long term use of high doses of celecoxib is associated with an increased cardiovascular toxicity. We discovered that the addition of curcumin, a natural COX-2 inhibitor, to celecoxib synergistically (up to 1000%) augments the growth inhibitory effects of celecoxib in in vitro and in vivo models of arthritis and cancer, thus rendering effective action of the drug at up to tenfold lower dose. This may pave the way for a novel strategy to treat arthritis and cancer because its effect [1] can be achieved in the serum of patients receiving standard anti-inflammatory or anti-neoplastic dosages of celecoxib, and [2] involves a regimen with a very low profile of side effects. Preliminary data suggest that the combination is not limited only to celecoxib and that addition of curcumin to other NSAIDs such as sulindac, synergistically augments neoplastic cell growth inhibition. Based on these findings we received an IRB approval to evaluate celecoxib+curcumin in patients with osteoarthritis, pancreatic cancer and metastatic CRC. We hope to complete these novel human clinical trials, in 12-18 months.

The androgen receptor (AR) plays a central role in the initiation and growth of prostate cancer. Androgen deprivation therapy (ADT) has been a gold standard for advanced prostate cancer for decades. Unfortunately, suppressive effects of ADT do not last long and hormone-refractory prostate cancer develops within several years. In spite of extensive research on mechanisms of hormoneindependent growth of prostate cancer, there are few effective treatment options for recurrent tumors and most patients die from the disease in a short period of time. Accumulating evidence suggests that the AR signaling system remains intact and activated despite low levels of androgens in hormone-resistant prostate cancer. Currently, modifications to the AR via mutations, amplification and phosphorylation have been proposed as underlying mechanisms of hormone-resistance of prostate cancer cells. In addition, changes in AR cofactors are implicated in ligandindependent activation of AR signaling. Thus, the development of novel and more effective treatment modalities targeting the AR and AR-related molecules may provide better management of androgen-independent prostate cancer. Although recent patents on the AR related to prostate cancer are focused on antiandrogens, future trend will be shifted to agents or methods suppressing molecules or pathways that activate AR signaling in low androgen environments.

The purine nucleoside analog (PNA) - cladribine (2-CdA, 2-chlorodeoxyadenosine) is a cytotoxic agent of high efficacy in lymphoid and myeloid malignancies. This drug was approved by the FDA for treatment of hairy cell leukemia and in some European countries for treatment of refractory/relapsed chronic lymphocytic leukemia. 2-CdA is usually administered as continuous or intermittent intravenous infusion. Recently however, new formulations of this agent have been developed for subcutaneous and oral administration. In contrast to other PNA, 2-CdA is equally cytotoxic to both proliferating and quiescent cells and several pathways may be responsible for the mechanism of its action. In addition, recent data indicate that 2-CdA combined with other cytotoxic agents and monoclonal antibodies show synergistic proapoptotic and cytotoxic activity on lymphoid and myeloid neoplastic cells. This review article summarizes recent achievements in the understanding of 2-CdA mechanism of action, pharmacokinetics of different pharmaceutical formulations and its approved and possible future applications in the treatment of hematological malignancies.

The most important recent patents concerning oral formulations of 2-CdA have been presented.

Cytotoxic nucleoside analogues are clinically important anticancer drugs. The newer member of this family, gemcitabine, has shown great activity in solid tumours and thus enlarged the spectra of malignancies treated by this family of molecules. However, the clinical use of nucleoside analogues is limited by important side-effects and primary or acquired drug resistance, and there is an unmet medical need for the development of new molecules and technologies allowing a suitable treatment of cancer patients with these agents. In this article we will review literature data and patents concerning (i) the recent development of some novel nucleoside analogues, (ii) oral formulations for cytotoxic nucleoside analogues, (iii) strategies to circumvent acquired resistance to nucleoside analogues, and (iv) gene therapy strategies used to increase cytotoxicity of nucleoside analogues.

Anti-cancer drug development is a major area of research. Monitoring of response to newer anti-cancer drugs has undergone an evolution from structural imaging modalities to target functional metabolic activity at cellular level to better define responsive and non-responsive cancerous tissue. This review article highlights the contribution of Positron Emission Tomography (PET) in this field. PET holds a promising role in the future by providing information pertaining to the drugs effectiveness early in the course of therapy, so that side effects and expenses can be reduced substantially. PET has been used to measure changes in drug induced metabolism, cellular proliferation and tissue perfusion. Also changes induced by immuno-modulating drugs such as apoptosis, telomere activity, growth factor levels and many more can be studied using specific radiolabelled PET tracers, whereas conventional imaging modalities that detect changes in tumour size and residual tissue histopathology may not prove useful in such scenario.

Hormone-dependent cancers of the breast, prostate and colon have, in the past decade, become the leading causes of morbidity and mortality. Billions of dollars have been spent to study cancers like these, and tremendous advancements in the understanding and treatment of cancer have been made. Nevertheless, as effective cures for a variety of cancers continue to elude us, natural protection against cancer has been receiving a great deal of attention lately not only from cancer researchers and patients, but also from physicians. Phytoestrogens, plantderived secondary metabolites, are diphenolic substances with structural similarity to naturally-occurring human steroid hormones. Phytoestrogens are normally divided into three main classes: flavonoids, coumestans and lignans. Flavonoids are found in almost all plant families in the leaves, stems, roots, flowers and seeds of plants, and are among the most popular anti-cancer candidates. Flavonoidic derivatives have a wide variety of biological actions that includes antibacterial, antiviral, anti-inflammatory, anticancer, and antiallergic activities. Some of these benefits are explained by the potent antioxidant effects of flavonoids, which include metal chelation and free-radical scavenging activities. However particular phytoestrogens show a marked ability to induce programmed cell death in specific cancer cells, and delay or prevent the onset of discrete cancers altogether. Patent applications regarding flavonoids range from protocols for extraction and purification from natural resources and the establishment of various biological activities for these extracts to novel methods for the production and isolation of flavonoids with known biological activities. This review will bring the reader up to date on the current knowledge and research available in the field of flavonoids and hormone-dependent cancers, and some of the submitted patents that exploit flavonoids.

Current standard treatments for cancer are associated with major doselimiting toxic effects on healthy tissue. The mucosal layers of the body are particularly sensitive to regimen-induced damage, with patients suffering many unpleasant and potentially life-threatening side-effects. In recent years, there has been an increase in the understanding of the pathobiology of regimen-related mucosal injury which has lead to a number of exciting inventions for its prevention and treatment being recently patented. Agents such as growth factors, cytokines, receptor agonists/antagonists and anti-inflammatory agents are among those in development in this emerging field. The complexity of mucosal injury poses a challenge for researchers, however, rational targeting of intervention strategies to critical mechanisms will lead to further progress.

While most anticancer agents are small molecular weight compounds that inhibit specific steps in the pathways contributing to cancer growth, or monoclonal antibodies that target specific antigens hyperexpressed in cancer cells, recent efforts have also been directed towards bacterial pathogens that are known to allow cancer regression. Consequently, patents that cover the construction or characterization of specific bacteria, with or without additional cloned genes, are available. This chapter is, however, focused on patents that claim bacterial proteins as potential anticancer agents. In particular, we describe two bacterial proteins that demonstrate both anticancer and antiviral, and often antiparasitic, activities, and therefore the patents cover multiple aspects of the potential use of such bacterial proteins in the treatment of not only cancer but also malaria or other parasitic diseases and HIV/AIDS and similar viral diseases. We also briefly discuss patents that cover the use of CpG-rich DNA, including bacterial DNA, as potential anticancer agents.

Cancer is one of the most dreaded diseases with a complex pathogenesis, which threats human life greatly. Multidisciplinary scientific investigations are making best efforts to combat this disease and put to the identification of novel anticancer agents. Patent anticancer agents registered in China are therefore increasing dramatically during the past ten years, which will be reviewed briefly in this article.

I. Platinum complexes

II. Anthracycline analogs (including doxorubicin derivatives)

III. Quinoline analogs

IV. Podophyllotoxins analogs

V. Taxane analogs

Targeting tumor angiogenesis to treat cancer has been the focus of intense research in recent decades. The resulting increase in our knowledge of cancer biology has lead to the development of several new classes of investigational agents that inhibit the angiogenic process. While many clinical trials on antiangiogenic compounds have had disappointing results, the recent approval of the first effective drug targeting tumor vessels has revived interest in further drug development for angiogenesis inhibitors. Of the plethora of new patents for antiangiogenic compounds, only a few describe compounds that will become effective and with tolerable toxicity therapies for patients with cancer. This review examines representative patents related to cancer angiogenesis in the context of our current knowledge of the biological processes leading to tumor vascularization and explores the future of multi-targeted therapy in the field of angiogenic therapy.

Cancer is a common disease in Western society that can affect any organ system. It has a high morbidity and mortality despite advances in treatment over the last hundred years. There is a clear need for new approaches to cancer chemotherapy including the possibility of reducing systemic adverse effects associated with current treatments. Vesicle trafficking is an essential cellular process that is perhaps not fully recognized. There is mounting evidence that vesicle trafficking, including the release of extracellular microvesicles, is a highly important process in tumourigenesis. Diverse aspects of tumourigenesis including invasion, metastasis, cell cycle regulation, angiogenesis, tumour immune privilege, neoplastic coagulopathy and multidrug resistance can be explained by altered vesicle trafficking in cancer cells. This paper reviews the evidence in the scientific and patent literature for the role of vesicle trafficking in tumourigenesis and suggests a number of targets and strategies that may be important for cancer therapeutics.