Current Drug Metabolism - Volume 16, Issue 6, 2015

Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug antitumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.

Nucleic acid based drugs (NADBs) are short DNA/RNA molecules that include among others, antisense oligonucleotides, aptamers, small interfering RNAs and micro-interfering RNAs. Despite the different mechanisms of actions, NABDs have the ability to combat the effects of pathological gene expression in many experimental systems. Thus, nowadays, NABDs are considered to have a great therapeutic potential, possibly superior to that of available drugs. Unfortunately, however, the lack of effective delivery systems limits the practical use of NABDs. Due to their hydrophilic nature, NABDs cannot efficiently cross cellular membrane; in addition, they are subjected to fast degradation by cellular and extracellular nucleases. Together these aspects make the delivery of NABDs as naked molecules almost un-effective. To optimize NABD delivery, several solutions have been investigated. From the first attempts described in the beginning of the 1980s, a burst in the number of published papers occurred in the beginning of 1990s reaching a peak in 2012-13. The extensive amount of work performed so far clearly witnesses the interest of the scientific community in this topic. In the present review, we will concentrate on the description of the most interesting advances in the field. Particular emphasis will be put on polymeric and lipid materials used alone or in combination with a promising delivery strategy based on the use of carbon nanotubes. The data presented suggest that, although further improvements are required, we are not far from the identification of effective delivery systems for NABDs thus making the clinical use of these molecules closer to reality.

Taxanes introduction in the mid 90s leads to significant advancement as well as superlative improvement in the treatment of cancer. Since then, several strategies have been designed to enhance therapeutic potential of these agents by overcoming the limitations in drug delivery and pharmacokinetic constraints associated with conventional delivery. In this regard, controlled drug delivery systems for taxanes have contributed enormously by altering the pharmacokinetic profile, thus ultimately enhancing their therapeutic response. With their conferred stellar merits, controlled drug delivery systems have been able to surmount many of the challenges associated with conventional drug delivery systems. The altered absorption, resistance, low toxicity and cellular uptake profiles that lead to better safety from variegated carrier systems like nanocarriers, liposomes, solid lipid nanoparticles, nanoemulsions, nanocapsules, hydrogels and micelles for controlled delivery of taxanes call for an exhaustive review for future progressive work. Therefore, this review focuses on the altered pharmacokinetic, pharmacodynamic and toxicity patterns achieved from various controlled drug delivery approaches, with the latter half highlighting the clinical profile set ups and commercial aspects of controlled release drug delivery systems.

Human organic anion transporting polypeptide 1B3 (OATP1B3) is a hepatocyte drug transporter that facilitates uptake of various therapeutic drugs from the circulatory system. Shortly after its initial identification in the liver, OATP1B3 expression was also reported in various solid cancer tissues. In the years since that time, it has been presumed that the OATP1B3 expressed in cancer tissues is identical to that expressed in the liver. However, we have recently identified a new OATP1B3 mRNA variant in cancer tissues, which we have named cancer-type OATP1B3 (Ct-OATP1B3). Given that the identification of Ct-OAT1B3 as a bona fide cancer-associated isoform revises a longstanding study premise, it is essential to fully elucidate the molecular function of Ct-OATP1B3 in cancer cells. Based on the predicted Ct-OATP1B3 protein structure, it is reasonable to assume that it functions as a transporter, but there are a number of ongoing arguments regarding Ct-OATP1B3 protein expression and its functions. With the above points in mind, this review will summarize current knowledge of Ct-OATP1B3 mRNA expression features in cancer tissues and its proposed, yet currently controversial, functions. Based on that background, our future perspectives related to Ct-OATP1B3 studies will also be presented.

Diallyl sulfide (DAS) and other organosulfur compounds are chief constituents of garlic. These compounds have many health benefits, as they are very efficient in detoxifying natural agents. Therefore, these compounds may be useful for prevention/treatment of cancers. However, DAS has shown appreciable allergic reactions and toxicity, as they can also affect normal cells. Thus their use as in the prevention and treatment of cancer is limited. DAS is a selective inhibitor of cytochrome P450 2E1 (CYP2E1), which is known to metabolize many xenobiotics including alcohol and analgesic drugs in the liver. CYP2E1-mediated alcohol/drug metabolism produce reactive oxygen species and reactive metabolites, which damage DNA, protein, and lipid membranes, subsequently causing liver damage. Several groups have shown that DAS is not only capable of inhibiting alcohol- and drug-mediated cellular toxicities, but also HIV protein- and diabetes-mediated toxicities by selectively inhibiting CYP2E1 in various cell types. However, due to known DAS toxicities, its use as a treatment modality for alcohol/drug- and HIV/diabetes-mediated toxicity have only limited clinical relevance. Therefore, effort is being made to generate DAS analogs, which are potent and selective inhibitor of CYP2E1 and poor substrate of CYP2E1. This review summarizes current advances in the field of DAS, its anticancer properties, role as a CYP2E1 inhibitor, preventing agent of cellular toxicities from alcohol, analgesic drugs, xenobiotics, as well as, from diseases like HIV and diabetes. Finally, this review also provides insights toward developing novel DAS analogues for chemical intervention of many disease conditions by targeting CYP2E1 enzyme.