Advances and challenges in hereditary cancer pharmacogenetics

Introduction: Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events.

Areas covered: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Moreover, the association between genetic variants of drug transporters with the clinical outcome is comprehensively discussed.

Expert opinion: Precision therapy in the field of oncology is developing tremendously. There are a number of somatic tumor genetic markers that are indicative for treatment with anti-cancer drugs. By contrast, for some hereditary variants, recommendations have been developed. Although we have vast knowledge on the association between drug transporter variants and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. Further developments in research may lead to the discovery of rare, but functionally relevant single nucleotide polymorphisms and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.     

Current trends in the use of vitamin E-based micellar nanocarriers for anticancer drug delivery

Introduction: Owing to the complexity of cancer pathogenesis, conventional chemotherapy can be an inadequate method of killing cancer cells effectively. Nanoparticle-based drug delivery systems have been widely exploited pre-clinically in recent years.

Areas covered: Incorporation of vitamin-E in nanocarriers have the advantage of (1) improving the hydrophobicity of the drug delivery system, thereby improving the solubility of the loaded poorly soluble anticancer drugs, (2) enhancing the biocompatibility of the polymeric drug carriers, and (3) improving the anticancer potential of the chemotherapeutic agents by reversing the cellular drug resistance via simultaneous administration. In addition to being a powerful antioxidant, vitamin E demonstrated its anticancer potential by inducing apoptosis in various cancer cell lines. Various vitamin E analogs have proven their ability to cause marked inhibition of drug efflux transporters.

Expert opinion: The review discusses the potential of incorporating vitamin E in the polymeric micelles which are designed to carry poorly water-soluble anticancer drugs. Current applications of various vitamin E-based polymeric micelles with emphasis on the use of α-tocopherol, D-α-tocopheryl succinate (α-TOS) and its conjugates such as D-α-tocopheryl polyethylene glycol-succinate (TPGS) in micellar system is delineated. Advantages of utilizing polymeric micelles for drug delivery and the challenges to treat cancer, including multiple drug resistance have been discussed.     

Approaches for multi-gram scale isolation of enantiomers for drug discovery

Introduction: Over the last 30 years, the scientific community has directed its efforts towards the identification of enantioselective approaches to obtain the desired active enantiomer. Accordingly, efficient production of single enantiomers from small to large scale, throughout Drug Discovery (DD) programs, has become of great interest and a fundamental challenge.

Areas covered: This review focuses on two fundamental strategies for preparing enantiomers in high yields and with an excellent enantiomeric excess (ee). Separation of racemates, enantioselective synthesis procedures, and integrated approaches have been extensively reviewed, to offer a guide that enables the selection of the suitable methodology for producing pure enantiomers in scales from small to large.

Expert opinion: Over the past two decades, drug regulatory agencies have set strict rules on the use of racemates and pure enantiomers, leading to the transformation of the drug market. Indeed, the number of drugs approved as a single enantiomer has exponentially increased, outclassing the racemic compounds. As a consequence, the academia and pharmaceutical companies are eager to develop efficient procedures for obtaining enantiopure compounds on the desired scale.