The dose-delivery schedule of conventional chemotherapy, which determines its efficacy and toxicity, is based on the maximum tolerated dose. This strategy has lead to cure and disease control in a significant number of patients but is associated with significant short-term and long-term toxicity. Recent data demonstrate that moderately low-dose chemotherapy may be efficiently combined with immunotherapy, particularly with dendritic cell (DC) vaccines, to improve the overall therapeutic efficacy. However, the direct effects of low and ultra-low concentrations on DCs are still unknown. Here we characterized the effects of low noncytotoxic concentrations of different classes of chemotherapeutic agents on human DCs in vitro. DCs treated with antimicrotubule agents vincristine, vinblastine, and paclitaxel or with antimetabolites 5-aza-2-deoxycytidine and methotrexate, showed increased expression of CD83 and CD40 molecules. Expression of CD80 on DCs was also stimulated by vinblastine, paclitaxel, azacytidine, methotrexate, and mitomycin C used in low nontoxic concentrations. Furthermore, 5-aza-2-deoxycytidine, methotrexate, and mitomycin C increased the ability of human DCs to stimulate proliferation of allogeneic T lymphocytes. Thus, our data demonstrate for the first time that in low noncytotoxic concentrations chemotherapeutic agents do not induce apoptosis of DCs, but directly enhance DC maturation and function. This suggests that modulation of human DCs by noncytotoxic concentrations of antineoplastic drugs, i.e. chemomodulation, might represent a novel approach for up-regulation of functional activity of resident DCs in the tumor microenvironment or improving the efficacy of DCs prepared ex vivo for subsequent vaccinations.

Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs.

Nucleos(t)ide analogues play pivotal roles as antiviral, cytotoxic or immunosuppressive agents. Here, we review recent reports of nucleoside analogues that exhibit broad-spectrum activity towards multiple life-threatening RNA and DNA viruses. We also present a discussion about nucleoside antimetabolites-approved antineoplastic agents-that have recently been shown to have antiviral and/or antibacterial activity. The approved drugs and drug combinations, as well as recently identified candidates for investigation and/or experimentation, are discussed. Several examples of repurposed drugs that have already been approved for use are presented. This strategy can be crucial for the first-line treatment of acute infections or coinfections and for the management of drug-resistant strains.

While gemcitabine (2'-2'-difluoro-2'-deoxycytidine, dFdC) displays wide-ranging antineoplastic activity as a single agent, variable response rates and poor intracellular metabolism often limit its clinical efficacy. In an effort to enhance dFdC cytotoxicity and help normalize response rates, we created a bifunctional fusion enzyme that combines the enzymatic activities of deoxycytidine kinase (dCK) and uridine/cytidine monophosphate kinase (UCMK) in a single polypeptide. Our goal was to evaluate whether the created fusion could induce beneficial, functional changes toward dFdC, expedite dFdC conversion to its active antimetabolites and consequently amplify cell dFdC sensitivity. While kinetic analyses revealed the UCMK/dCK fusion enzyme to possess both native activities, the fusion rendered cells sensitive to the cytotoxic effects of dFdC at the same level as dCK expression alone. These results suggest that increased wild-type UCMK expression does not provide a significant enhancement in dFdC-mediated cytotoxicity and may warrant the implementation of studies aimed at engineering UCMK variants with improved activity toward gemcitabine monophosphate.

Despite the available prevention and early detection strategies, squamous-cell carcinoma of the uterine cervix is still diagnosed as locally advanced disease in a considerable proportion of patients. As a potent sensitizer of cancer cells, cisplatin has been the "traditional partner" of external beam irradiation in this setting for more than two decades. Induction chemotherapy strategies followed by concurrent chemoradiation or surgery and preoperative concurrent chemoradiation have been recently implemented in clinical trials in an effort to optimize local control and to minimize the risk of distant metastases. In this context, cisplatin has been combined with a number of other potential radiosensitizers, including 5-fluorouracil, capecitabine, and gemcitabine. In patients resistant or intolerant to platinum compounds, numerous non-platinum-containing regimens have been developed, implementing various antimetabolites, taxanes, antineoplastic antibiotics, and topoisomerase II inhibitors. More recently, molecular agents targeting critical pathways in cervical malignant transformation are being assessed in early clinical trials in combination with external-beam irradiation. In the current work, we review the evolving role of cisplatin and other platinum compounds, either alone or in combination regimens, in the context of other potent radiosensitizers. The emerging role of molecular targeted agents, as candidate partners of external beam irradiation, is also discussed.