Frontiers in Drug Design and Discovery

Research specialized in the field of hematology oncology over relatively recent years has revolutionized patient care and led to an array of chemotherapeutic agents approved by the Food and Drug Administration. Both oral and intravenous drug formulations have been marketed, including targeted therapies, for several hematologic disorders including acute and chronic leukemias, Hodgkin and non-Hodgkin’s lymphomas, multiple myeloma, and myelofibrosis. The primary focus of this chapter will include latest chemotherapy developments in hematology covering critical topics of pharmacology, pharmacokinetics/pharmacodynamics, and pivotal clinical studies addressing both labeled and off-labeled indications. Lastly, future directions will be addressed, where applicable, in this continuously evolving clinical field.

Esophageal cancer (EC) is the 8th most common cause of cancer worldwide and is endemic in certain parts of the world, especially in developing countries. The etiology of EC is multifactorial and includes tobacco and alcohol abuse, obesity, chronic gastroesophageal reflux disease (GERD), and Barrett's esophagus. In addition, there are hereditary cancer syndromes associated with an increased risk of ECs. Histologically, EC is classified as either squamous cell carcinoma (ESCC) or adenocarcinoma (EAC). The western hemisphere has seen a shift in decreasing incidence of ESCC versus increasing incidence of EAC. Human epidermal growth factor receptor 2 (Her2) gene and Her2 protein expression have been implicated in the pathogenesis of esophageal cancer. A multidisciplinary approach to EC is essential for workup, management, and treatment. Current therapeutic modalities include endoscopic treatments, such as endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and ablation of early stage disease for both ESCC and EAC. For locally advanced disease, neoadjuvant chemotherapy and radiation followed by surgical resection are often used. However, the performance status of the patient as being “medically fit” versus “unfit” also plays an instrumental role in determining treatment. For metastatic EC, palliative chemotherapy remains the sole treatment. Most recently, there has been interest in moving beyond standard cytotoxic chemotherapy and to explore novel agents including immunotherapy, which could result in more promising outcomes in this malignancy.

In the past, androgen deprivation therapy (ADT) was used for the conservative treatment of prostatic cancer, but now also used in the setting of neoadjuvant and adjuvant treatment in combination with radiotherapy. Another use is for loco-regional or distant recurrence after primary treatment of surgery or radiotherapy. ADT is an alternative for local failure after radical treatment and it compares favorably with cryotherapy or high-intensity focused ultrasound therapy. Traditionally gonadotropin releasing hormone (GnRH) agonists are used. A new class of agent in clinical use is the gonadotrophin antagonist degarelix. Newer choices for castrate resistant prostate cancer include abiraterone and enzalutamide. The emphasis of this review is on drug discovery, design and clinical trials. The indication and rationale for choosing the appropriate first and second line drugs will be discussed for easy access at point of care. This chapter summarizes the recent developments and the controversies to be explored in the future which will be of interest to all health care professionals, colleagues in the pharmaceutical industry, family physicians, urologists, radiation and medical oncologists. We also add our clinical experience of use of different ADT throughout this review to make it practical for bedside management. Common questions from physicians and patients are answered in this review.

Over the last 5 decades, biologically active compounds derived from natural resources have provided a number of useful cancer chemotherapeutic drugs. The search for natural product based drug candidates is growing rapidly with the advancements in drug discovery and development techniques in recent years, with the active fractions and isolates of marine organisms along with terrestrial plants. Microorganisms are also being explored for their anti-cancer activities. The present review highlights the information about occurrence, types, clinical features pathophysiology and etiology of cancer as well as conventional and recent advancements in anticancer drug development along with description of selected medicinal plants and compounds derived from natural sources or their derivatives with potential use as cancer chemotherapeutic agents. It is expected that such promising leads from natural origin tend to create extensive interest among researchers including medicinal chemists and pharmacologists working in anticancer drug research and therefore the availability of a given brief information about cancer and anticancer drug development focused on natural product may be proved useful to develop preliminary ideas of biochemical pathways and key enzymes regulating these pathways as well as new targets involved in different stages of the disease along with chemotherapeutic agents which selectively target a specific signaling pathway through structure-activity relationships and preclinical trials.

Polyhydroxyalkanoates (PHAs) are the natural polymers that have been a subject of a significant research interest in the past few decades. The PHAs (natural as well as their synthetic analogs) as biodegradable and biocompatible polymers were studied intensively for biomedical applications, that is, scaffolds for tissue engineering. Drug-loaded implants or scaffolds based on these polyesters were also used in the drug release systems. Drug delivery systems should provide an optimal release profile of an active compound that allows to increase therapeutic effect, decrease side effects, and improve patient convenience and compliance. Therefore, recently, the increasing interest is focused on the use of PHA as drug carriers because of significant improvement in the bioavailability of bioactive substances. Recent developments introduced such strategies as conjugation of the drug with low-molecular-weight poly(3-hydroxybutyrate) or preparation of PHA particles loaded with the drug. On the contrary, there is a growing interest in functionalized PHA technology. The advancement of these strategies allows to obtain the targeting systems based on the chemical modification, for example, by folic acid attachment or biosynthesis of targeting proteins on the PHA particle surface. In addition, the PHAs were presented as materials that could be used in transdermal administration of bioactive substances for medical or cosmetic purposes. The development of novel functionalized PHAs has opened new possibilities to combine good biocompatibility of PHA-based drug delivery systems with improved drug loading and release properties, targeting, or imaging possibilities. Further progress in PHA-based drug delivery systems is expected because of the combination of excellent biocompatibility of these biopolymers and strong beneficial effect on drug administration.