Frontiers in Drug Design and Discovery

Chemotherapy drugs are long being used to treat cancer either as single drug or in combination with other treatment strategies. However, the current problem with treatment is the development of chemo-resistance properties of cancer cells that causes relapses at the later stages of the treatment. It is therefore necessary to design and develop new drugs or modify existing treatment strategies. Cancer cells show abnormal cell growth and adopt metabolic pathways that are different from normal cells. There are also links between metabolic pathways and chemo-resistance development in cancer cells. This indicates the importance of integration of knowledge on the metabolic pathways of cancer cells prior to new drug design and development for cancer treatment. In this review, we discuss the metabolic pathways associated with chemo-resistance development and focus on existing or new drugs targeting these pathways.

The extensive use of chemotherapy in clinical practice has led to considerable controversy due to their potential adverse cardiovascular effects in surviving cancer patients. Among the effects of chemotherapeutic agents on the cardiovascular system, the most frequent and serious is heart failure with ventricular systolic dysfunction. Other harmful effects include hypertension, thromboembolic disease, pericardial disease, arrhythmias and myocardial ischemia. Cancer therapyinduced cardiomyopathy was almost exclusively associated with the use of cumulative doses of anthracyclines. However, new therapeutic agents, such as the monoclonal antibody trastuzumab, induce transient reversible myocyte dysfunction. Recent research to limit cardiotoxicity has focused on early monitoring and risk stratification to identify patients that are ‘at risk’ for cardiotoxicity, using biochemical markers and the prophylactic use of novel cardioprotective agents. This chapter reviews the clinical course, pathogenesis, cardiac monitoring and new concepts in diagnosing and preventing chemotherapy cardiotoxicity.

Drug resistance and poor efficacy of anticancer therapies prompt to investigate innovative therapeutic strategies aimed to improving efficacy and lowering toxicity. Recent advances in chemotherapeutics have been achieved using specific pharmaceutical combinations or ameliorating drug delivery by drug encapsulation.

Novel combined treatments are based on the use of drugs, typically natural active or intended for other uses combined with the classical anti-cancer drug. These compounds promote synergistic effects even more enhanced when drug delivery is achieved by nanocarriers. Nanotechnologies provide a site-specific delivery at the tumor site, resulting from receptor-mediated endocytosis and prolonged circulation time. Nanocarriers also increase drug bioavailability and biocompatibility contributing to a drug increase inside the tumor and determining a minor toxicity and a better efficacy.

This chapter reports recent findings about novel anticancer combined treatments and about the latest drug delivery systems based on the use of nanocarriers.

Uterine sarcomas are relatively rare tumors, constituting only 8%-10% of all uterine malignancies. Its three most common histologic variants are carcinosarcoma (CS), leiomyosarcoma (LMS), and endometrial stromal sarcoma (ESS). Because of its frequent resistance to existing chemotherapeutic drugs (caused by several mechanisms), standard chemotherapeutic regimens have not yet been established. Presently, CSs are treated in the same way as high-grade endometrioid endometrial carcinomas. A combination of carboplatin and paclitaxel is the most commonly used adjuvant therapy regimen in advanced or recurrent CS. For LMS, the key drugs are doxorubicin, ifosfamide, gemcitabine, and docetaxel. These drugs are used as single agents or in combination for the treatment of patients with advanced or recurrent LMS. For ESS treatment, hormonal agents have been used because ESS expresses estrogen and progesterone receptors. Because of its rarity, well-designed random controlled trials are required for future investigations of the efficacy of chemotherapy for patients with uterine sarcoma.

A multi-target strategies targeting on various biochemical and physiological pathways implicated in tumour pathogenesis should be developed with the ultimate aim to manage patients with cancer and reduce the normal-tissue toxicity. Tumor angiogenesis has been recently discovered as an important strategy in treating cancer as most tumors rely on angiogenesis to survive, develop, invade and metastasize. Targeting angiogenesis to inhibit the progression of tumorigenesis has recently been a focus in developing novel anti-cancer development. This is mainly due to the specificity that anti-angiogenic possesses: it targets on newly-formed blood vessels and spares the existing ones. With that being said, inhibiting angiogenesis is now considered a promising strategy in the development and selection of new anti-cancer drug candidates. To date, there are cytotoxic drugs which also exhibit antiangiogenic activity but not angiogenesis inhibitors in whole. In this chapter, we will be discussing selected natural sources including marine products which have been investigated for their antiangiogenic activities. Various methods in validating the effects as well as their possible multiple pathways will also be contended in this chapter.

Clinically, personalized medicine also referred to as precision medicine is a new medical model to be directly tailored for the care of individual patients. It is often called "the right treatment for the right person at the right time." Most successful examples of personalized treatments require a rational clinical genomic analysis. Following Research and Development (R&D) of techniques and analysis of clinical genomic expression, genomic expression profile along with system modeling has been increasingly applied for personalized therapy. Now personalized chemotherapy, one of personalized therapy, has been brought forward to the field of cancer. According to protocol of personalized chemotherapy from tumor tissue sampling to clinical application in queue, I will introduce the entire process including clinical sampling, analyzing mRNA genomic expression level with its diagnosis, discovering gene expression signature by system modeling and uncovering sensitive drugs from drugbank for clinical application. At present, after next-generation sequencing is brought into the new field, system modeling related with drugs discovery will make great contribution for future personalized chemotherapy of tumor diseases.

Infectious diseases are increasingly becoming a major health concern annually afflicting millions of humans worldwide. Presently, the greatest challenge to any successful effective treatment of a particular pathogen is the emergence of drugresistance, less bioavailability and non-specificity of potent antibiotics at the target sites, requiring large doses of medicine over a longer period of time, resulting in maximum toxicity to patients. However, drug delivery is a powerful concept in nanomedicine which is constantly growing at a burgeoning pace, could provide an efficient alternative to target any pathogens at any site in the body using advanced combined nanoparticle platforms or nanocarriers with fewer side effects. Significantly, nanotherapeutics could be administered through various specific routes such as oral, parenteral, and topical for effective treatment.

In summary, this chapter would highlight the role of targeted antibiotics as an advancement of future nanomedicine over conventional therapeutics against virulent infectious diseases.