Review

Nucleoside and nucleobase transport systems of mammalian cells

Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a clinical challenge. Over one third of patients remain resistant to current pharmacological interventions. Moreover, even when effective in suppressing seizures, current medications are merely symptomatic without significantly altering the course of the disease. Much effort is therefore invested in identifying new treatments with novel mechanisms of action, effective in drug-refractory epilepsy patients, and with the potential to modify disease progression. Compelling evidence has demonstrated that the purines, ATP and adenosine, are key mediators of the epileptogenic process. Extracellular ATP concentrations increase dramatically under pathological conditions, where it functions as a ligand at a host of purinergic receptors. ATP, however, also forms a substrate pool for the production of adenosine, via the action of an array of extracellular ATP degrading enzymes. ATP and adenosine have assumed largely opposite roles in coupling neuronal excitability to energy homeostasis in the brain. This review integrates and critically discusses novel findings regarding how ATP and adenosine control seizures and the development of epilepsy. This includes purine receptor P1 and P2-dependent mechanisms, release and reuptake mechanisms, extracellular and intracellular purine metabolism, and emerging receptor-independent effects of purines. Finally, possible purine-based therapeutic strategies for seizure suppression and disease modification are discussed.

Cancer is a community health hazard which progress at a fatal rate in various countries across the globe. An agent used for chemotherapy should exhibit ideal properties to be an effective anticancer medicine. The chemotherapeutic medicines used for treatment of various cancers are, gemcitabine, paclitaxel, etoposide, methotrexate, cisplatin, doxorubicin and 5-fluorouracil. However, many of these agents present nonspecific systemic toxicity that prevents their treatment efficiency. Of all, gemcitabine has shown to be an active agent against colon, pancreatic, colon, ovarian, breast, head and neck and lung cancers in amalgamation with various anticancer agents. Gemcitabine is considered a gold-standard and the first FDA approved agent used as a monotherapy in management of advanced pancreatic cancers. However due to its poor pharmacokinetics, there is need of newer drug delivery system for efficient action. Nanotechnology has shown to be an emerging trend in field of medicine in providing novel modalities for cancer treatment. Various nanocarriers have the potential to deliver the drug at the desired site to obtain information about diagnosis and treatment of cancer. This review highlights on various nanocarriers like polymeric nanoparticles, solid lipid nanoparticles, mesoporous silica nanoparticles, magnetic nanoparticles, micelles, liposomes, dendrimers, gold nanoparticles and combination approaches for delivery of gemcitabine for cancer therapy. The co-encapsulation and concurrent delivery of Gem with other anticancer agents can enhance drug action at the cancer site with reduced side effects.

The initial conventional chemotherapy of colorectal cancer (CRC) always consists of a fluoropyrimidine, either the parent drug 5-fluorouracil (5FU), the prodrug capecitabine, or the triple combination S-1, in which Ftorafur serves as a prodrug for 5FU. Initially, 5FU was combined with leucovorin, which potentiates the inhibition of the target thymidylate synthase (TS). Since TS inhibition leads to depletion of TTP, essential for DNA synthesis, this results in an increased incorporation of dUTP into DNA, together leading to a so-called thymine-less death. In advanced CRC both low TS expression and a high inhibition are related to a longer survival of patients. Other resistance parameters include decreased intratumoral activation to its nucleotide, and increased systemic degradation by dihydropyrimidine dehydrogenase. In the commonly used combinations (FOLFIRI and FOLFOX) with the topoisomerase I inhibitor, irinotecan, and the DACH-modified platinum analog, oxaliplatin, the relation with TS became less clear. Resistance to irinotecan is mainly associated with its systemic degradation by cytochrome P450 enzymes or conjugation by the UDP-glucuronyl transferase, while resistance to oxaliplatin is associated with increased repair of oxaliplatin-DNA adducts by the repair enzyme ERCC1. With the introduction of capecitabine, the limiting activation catalyzed by carboxyl-esterase and cytidine deaminase was associated with resistance, although the last step in the activation to 5FU catalyzed by both uridine phosphorylase and thymidine phosphorylase (TP) has more often been associated with resistance. Recently, another fluoropyrimidine, TAS-102, containing trifluorothymidine, was registered as third-line treatment. For this drug, decreased cellular uptake by the equilibrative nucleoside transporter, activation by thymidine kinase 1, and decreased incorporation into DNA have been associated with resistance. Analysis of these parameters should enable to guide treatment.