Antiangiogenic,bioreductive and gene therapy approaches to the treatment of hypoxic tumours

Quinone based bioreductive drugs have, potentially, a very versatile use in cancer chemotherapy. They can be activated by DT-diaphorase and hence can be used to target tumour types rich in this (O2)-independent reductase enzyme. Small molecular modifications can substantially reduce specificity for DT-diaphorase and under these circumstances the quinones become much less toxic in air but retain their potent cytotoxic effects under hypoxic conditions. Our understanding of the reductive (bio) chemistry of indolequinones, in particular, has subsequently allowed us to develop a platform technology where almost any therapeutic entity can potentially be delivered, selectively, to hypoxic tumours. Antiangiogenic approaches are currently receiving a substantial amount of attention and this review brings their development into context in view of the hypoxia dependence for neovascularization. Lastly, the use of bioreductive drugs when combined with hypoxia-mediated gene therapy is described. Such an approach provides a unique dual level of specificity for targeting hypoxic tumours and potentially can provide substantial therapeutic benefit.     

Bipolar disorders: new approaches to therapy

This article reviews the evidence supporting different somatic treatment strategies in the acute and maintenance treatment phases of bipolar disorder. Bipolar affective disorder is a chronic disorder with a life time incidence of 0.3 - 1.5/100 [1]. Severe affective disorder is associated with a risk of completed suicide of 6 - 15% [2,3]. Traditionally, bipolar disorder has been considered as an episodic disorder with good inter-episode recovery [4]. This is being increasingly challenged with patients demonstrating social, marital, occupational and cognitive dysfunction, even when euthymic [5]. The management of bipolar disorder should be considered in the context of; the type of episode, this may be manic, depressed or mixed; the degree and rate of recovery; the cycling frequency and precipitant, if any, for recurrence and the onset and evolution of the underlying illness. On average, four episodes occur every 10 years. However 13 - 24% of patients develop rapid cycling disorder, in which four or more episodes occur within a year. Patients with bipolar disorder often have co-morbid anxiety and substance abuse. Moreover, axis I co-morbidity may be associated with an earlier age at onset and worsening course of bipolar illness. [6]. Axis II co-morbidity is also common, this was highlighted in a study by Kay and colleagues who, after excluding patients with a history of alcohol misuse, demonstrated axis II co-morbidity in almost a quarter of euthymic bipolar patients [7]. Good practice relies on an overall management plan that incorporates somatic, psychological and social approaches. This paper will focus on one element of such a plan, the currently available somatic management strategies for bipolar disorder.     

Antiangiogenic and antivascular therapy for cancer.

The great interest in the potential antineoplastic effect of targeting tumor-associated blood vessels has generated an expanding armamentarium of therapeutic tools that include antiangiogenic compounds, aimed at preventing the formation of vessels, and antivascular compounds, targeted to the existing tumor vasculature. Following promising preclinical studies, antiangiogenic drugs have rapidly gained access to clinical trials.     

Synthetic approaches to the 2006 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 16 NCEs marketed in 2006.     

Synthetic approaches to the 2004 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as leads for designing future drugs. To this end, this review covers the syntheses of 12 NCEs marketed in 2004.     

Synthetic approaches to the 2003 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing new future drugs. To these ends, this review covers the syntheses of 23 NCEs marketed in 2003.     

Pathogenesis and clinical approaches to anticonvulsant hypersensitivity syndrome: current state of knowledge

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, but severe and potentially fatal, adverse reaction that occurs in patients who are treated with commonly used older anticonvulsant drugs (phenytoin, carbamazepine and phenobarbital) and/or with some newer agents (lamotrigine). Paediatric patients are at an increased risk for the development of AHS for the higher incidence of seizure disorder in the first decade of life. Hypersensitivity reactions range from simple maculopapular skin eruptions to a severe life-threatening disorder. AHS is typically associated with the development of skin rash, fever and internal organ dysfunctions. Recent evidence suggests that AHS is the result of a chemotoxic and immunologically-mediated injury, characterized by skin and mucosal bioactivation of antiepileptic drugs and by major histocompatibility complex-dependent clonal expansion of T cells. Early recognition of AHS and withdrawal of anticonvulsant therapy are essential for a successful outcome. In vivo and vitro tests can be helpful for the diagnosis that actually depends essentially on clinical recognition.     

Synthetic approaches to the 2002 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. Therefore, it is important to be acquainted with these new structures as well as their syntheses. To these ends, this review covers the syntheses of 28 NCEs marketed in 2002.     

Synthetic approaches to the 2005 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 22 NCEs marketed in 2005.     

Emerging drugs to replace current leaders in first-line therapy for breast cancer

Increasing knowledge of drug resistance and side effects of currently approved agents, and of the biology of breast cancer, has given way to new treatment options that improve on previously available agents, or medications that target specific kinases and proteins associated with an oncogenic phenotype. This paper discusses new agents, including improved formulations of paclitaxel and epothilones, and molecularly targeted agents such as bevacizumab, sunitinib malate, pertuzumab, lapatinib, the mTOR inhibitors and farnesyl transferase inhibitors. Although endocrine therapy is a targeted therapy, it is not covered in this paper. These agents have increased excitement in the treatment of breast cancer and stand on the forefront of a potential improvement in quality of life and treatment options for patients afflicted with this deadly disease.     

Intrabody-based approaches to cancer therapy: status and prospects

Continuing developments from the study of cancer at the molecular level are yielding increasing numbers of targets that may be used for therapeutic intervention. Advances in the field of antibody engineering over the past several decades have given scientists the capability of directing the highly specific interaction of antibodies with antigens inward, to the intracellular compartments of living cells. These intracellular antibodies, i.e., intrabodies, are being developed to bind to, neutralize, or modify the function or localization of cancer-related targets and thereby affect the malignant phenotype. This has resulted in a promising new tool for the study and treatment of cancer. Due to recent advances in the development of the antibody engineering technologies, increasing numbers of intrabodies are being exploited to a growing list of cancer-related, as well as other disease targets. There are still, however, many technical issues, particularly related to clinical applications of the intrabodies, that must be addressed before the full promise of this class of therapeutic agent is realized. This review will focus on the recent progress in the generation and use of intrabodies in the field of oncology. The technical issues associated with their further development will also be discussed.     

Antiangiogenic drugs and tyrosine kinases

Various cancer types have different molecular and biological strategies for vascularization: neoangiogenesis, postnatal vasculogenesis, glomeruloid angiogenesis, intussusceptive microvascular growth, vessel cooption and vascular mimicry. The majority is still relatively obscure, which limits the development of more successful antivascular agents. It is not a surprise that, as our knowledge is deepest in case of tumor-induced neoangiogenesis, the first successful antiangiogenic drugs have been developed in this area. As neoangiogenesis involves growth factor receptors, most of them tyrosine kinases (KIT, Flt-3, VEGFRs, PDGFR, TIE2, FGFR1, EGFR and MET), several of these novel agents are tyrosine kinase inhibitors. This review summarizes our recent knowledge on various forms of cancer vascularization, the molecular mechanisms behind, depicting the "drugable" targets. In a short overview, we demonstrate the array of antiangiogenic approaches focusing on the tyrosine kinase inhibitors and summarize their preclinical activities. Finally we review the clinically available antiangiogenic tyrosine kinase inhibitors and demonstrate their current application and future perspectives. Further development in this field may depend on the identification of novel inhibitors targeting kinases that cannot be modulated yet by the available agents and on the development of vascularization strategy-specific design of these antivascular therapies.     

Molecular approaches to cervical cancer therapy

Cervical cancer is the second most common malignancy in women worldwide. Two HPV strains, HPV-16 and 18, occur in the 70% of untreated cancers. Expression of viral oncogenes E6 and E7 disrupt the cell cycle by interfering with p53 and p107(Rb). It is known that HPV infection is necessary but insufficient to cause malignancy. Furthermore, persistence of HPV-16 or 18 in women does not necessarily result in cancer. Persistence indicates the importance of other factors for malignant conversion of high-grade HPV infection. The multi-step cervical carcinogenesis process is amendable to molecular therapeutics such as therapeutic nucleic acids (TNAs). TNA-based therapies for cervical carcinoma include ribozymes, antisense oligonucleotides (AS-ODNs) and small interfering RNAs (siRNAs). In vitro experiments with TNAs successfully inhibited E6/E7 expression and caused induction of apoptosis and/or senescence in cervical carcinoma cells. Early ribozyme and AS-ODN approaches showed promise as therapeutic moieties for cervical cancer. Despite the very high in vitro efficiency of siRNA-based therapies they present the same issues that burdened clinical development of ribozymes and AS-ODNs. These issues include intracellular target accessibility, specificity and delivery. Ribozymes are useful for functional genomic studies including diagnosis. Moreover, AS-ODNs appear better suited for clinical protocols because recent advances in nucleic acid chemistry allow higher cell uptake with very low off-target effects leading to actual AS-ODNs clinical applications. By using combined treatments with multiple targets it will be possible to apply TNAs directly to the cancerous cervix to destroy viral RNA and obliterate the tumor.     

Antimalarial drugs: current status and new developments

Malaria continues to be a major threat in the developing world, with > 1 million clinical episodes and 3000 deaths every day. In the last century, malaria claimed between 150 and 300 million lives, accounting for 2 – 5% of all deaths. Currently ~ 40% of the world population resides in areas of active malaria transmission. The disease symptoms are most severe in young children and pregnant women. A total of 90% of the disease-associated mortality occurs in Subsaharan Africa, despite the fact that malaria is indigenous to most tropical regions. A licensed vaccine for malaria has not become a reality and antimalarial drugs are the only available method of treatment. Although chloroquine, the first synthetically developed antimalarial, proved to be an almost magical cure for > 30 years, the emergence and spread of chloroquine-resistant parasites has made it virtually ineffective in most parts of the world. Currently, artemisinin, a plant-derived antimalarial, is the only available drug that is globally effective against the parasite. Although several new drugs have been introduced in the past 30 years, widespread or isolated cases of resistance indicate that their window of effectiveness will be limited. Thus, there is an urgent need to develop new therapeutics and regimens for malaria control. This article presents an overview of the currently available antimalarial chemotherapy options and the efforts being undertaken to develop new drugs based on both the recent technological advances and modifications to the old remedies, and on combination therapies.     

Antimalarial drugs: current status and new developments

Malaria continues to be a major threat in the developing world, with > 1 million clinical episodes and 3000 deaths every day. In the last century, malaria claimed between 150 and 300 million lives, accounting for 2 - 5% of all deaths. Currently approximately 40% of the world population resides in areas of active malaria transmission. The disease symptoms are most severe in young children and pregnant women. A total of 90% of the disease-associated mortality occurs in Subsaharan Africa, despite the fact that malaria is indigenous to most tropical regions. A licensed vaccine for malaria has not become a reality and antimalarial drugs are the only available method of treatment. Although chloroquine, the first synthetically developed antimalarial, proved to be an almost magical cure for > 30 years, the emergence and spread of chloroquine-resistant parasites has made it virtually ineffective in most parts of the world. Currently, artemisinin, a plant-derived antimalarial, is the only available drug that is globally effective against the parasite. Although several new drugs have been introduced in the past 30 years, widespread or isolated cases of resistance indicate that their window of effectiveness will be limited. Thus, there is an urgent need to develop new therapeutics and regimens for malaria control. This article presents an overview of the currently available antimalarial chemotherapy options and the efforts being undertaken to develop new drugs based on both the recent technological advances and modifications to the old remedies, and on combination therapies.     

Insulin-like growth factor: current concepts and new developments in cancer therapy

The insulin-like growth factor (IGF) family and the IGF-1 receptor (IGF-1R) play an important role in cancer. This intricate and complex signaling pathway provides many opportunities for therapeutic intervention, and several novel therapeutics aimed at the IGF-1R, particularly monoclonal antibodies and small molecule tyrosine kinase inhibitors, are under clinical investigation. This article provides a patent overview of the IGF signaling pathway and its complexity, addresses the justification for the use of IGF-1R-targeted therapy, and reviews the results of in vivo and in vitro novel therapeutics. Over the past year, the completion of several phase I, II, and III trials have provided interesting new information about the clinical activity of these novel compounds, particularly CP-751,871, IMC-A12, R1507, AMG-479, AVE-1642, MK-0646, XL-228, OSI-906, and BMS-754807. We review the important preliminary results from clinical trials with these compounds and conclude with a discussion about future therapeutic efforts.