Oral mucositis on a chip: modeling induction by chemo- and radiation treatments and recovery.

Oral mucositis (OM) is a debilitating complication affecting roughly 70% of head and neck cancer patients receiving chemotherapy and/or radiation treatment. No broadly effective preventative treatment for OM exists. Therefore, anin vitromodel of cancer treatment-induced OM would aid studies into possible origins of the pathology and future drug targets to ameliorate it. In this study, we present a microfluidic oral mucosa triculture tissue construct consisting of a keratinocyte layer attached to a subepithelial fibroblast and endothelial cell-embedded collagen gel. To address the typically low stability of mucosal constructs in microfluidics, ruthenium-catalyzed photocrosslinking was implemented to strengthen the collagen gel and prevent the invasion of keratinocytes, thus maintaining tissue construct geometry and oral mucosa barrier function for over 18 d of culture. Next, the OM chip was exposed to cisplatin (day 10) and damaging radiation (day 11, ± cisplatin at day 10), mimicking damage from cancer therapy. Damage to and then recovery of the tissue layers and function were observed over days 11-18. Therefore, several important features of OM induction and resolution were modeled in microfluidic culture. The OM model on a chip allows for more sophisticated studies into mechanisms of OM and potential treatments.

RuII( p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo.

Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru( p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru( p-cymene)(Cl)(µ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV-vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru( p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity.

Comparative solution equilibrium and structural studies of half-sandwich ruthenium(II)(η6-toluene) complexes of picolinate derivatives.

Five Ru(II)(η6-toluene) complexes formed with 2-picolinic acid and its various derivatives have been synthesized and characterized. X-ray structures of four complexes are also reported. Complex formation processes of [Ru(II)(η6-toluene)(H2O)3]2+ organometallic cation with the metal-free ligands were studied in aqueous solution in the presence of chloride ions by the combined use of 1H NMR spectroscopy, UV-visible spectrophotometry and pH-potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with in vitro cytotoxic and antiproliferative activity in cancer cell lines being sensitive and resistant to classic chemotherapy and in normal cells as well. Formation of mono complexes such as [Ru(η6-toluene)(L)(Z)]+/0 (L: completely deprotonated ligand; Z = H2O/Cl-) with high stability and [Ru(η6-toluene)(L)(OH)] was found in solution. The pKa values (8.3-8.7) reflect the formation of low amount of mixed hydroxido species at pH 7.4 at 0.2 M KCl ionic strength. The complexes are fairly hydrophilic and show moderate chloride ion affinity and fast chloride-water exchange processes. The studied complexes exhibit no cytotoxic activity in human cancer cells (IC50 > 100 µM), only complexes formed with 2-picolinic acid (1) and its 3-methyl derivative (2) represented a moderate antiproliferative effect (IC50 = 84.8 (1), 79.2 µM (2)) on a multidrug resistant colon adenocarcinoma cell line revealing considerable multidrug resistant selectivity. Complexes 1 and 2 bind to human serum albumin covalently and relatively slowly with moderate strength at multiple binding sites without ligand cleavage.

DEEP, SHALLOW AND EYE LENS DOSES FROM 106Ru/106Rh-A COMPARSION.

106Ru/106Rh is unique amongst other commonly used beta sources such as 147Pm, 85Kr, 204Tl, 32P, natU and 90Sr/90Y in the sense that it is capable of simultaneously delivering shallow/skin, eye lens and deep/whole body doses (WBDs) and they differ from each other substantially. In view of this, the investigation of various quantities defined for individual monitoring is possible and this makes 106Ru/106Rh beta source, a classical example in radiation protection and dosimetry. This led us to estimate skin, eye lens and WBDs for 106Ru/106Rh beta source. Optically stimulated luminescence based ultra-thin α-Al2O3:C disc dosimeters were used in the present study. Typical values (relative) of the eye lens and whole body/deep doses with respective to the skin dose (100%) were experimentally measured as ~66 ± 4.6% and 17 ± 3.9%, respectively. The study shows that 106Ru/106Rh beta source is capable of delivering even WBD which is not the case with other beta sources.

Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy.

BACKGROUND: This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment. METHODS: Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m(2) at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m(2) at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored. At the maximal tolerable dose level of this schedule an expansion group was enrolled of which 15 patients were evaluable for response. RESULTS: Due to frequent neutropenic dose interruptions in the third week, the 28 day schedule was amended into a 21 day schedule. The maximal tolerable dose was 300 and 450 mg/m(2) of NAMI-A (21 day schedule). Main adverse events consisted of neutropenia, anemia, elevated liver enzymes, transient creatinine elevation, nausea, vomiting, constipation, diarrhea, fatigue, and renal toxicity. CONCLUSION: NAMI-A administered in combination with gemcitabine is only moderately tolerated and less active in NSCLC patients after first line treatment than gemcitabine alone.

Results after beta-irradiation (106Ru/106Rh) of choroidal melanomas. Twenty years' experience.

For two decades, from 1964 to 1984, 309 patients suffering from choroidal melanoma were treated with 106Ru/106Rh applications, following confirmation of diagnosis by a variety of tests. A total of 216 patients (69.9%) were treated successfully and have been under observation for a mean period of 6.7 years after irradiation. 188 patients were followed for more than five years. Results indicate that enucleation for choroidal melanoma, especially in cases of eyes with good vision, may no longer be the standard treatment for this disease. This appears particularly true inasmuch as almost 50% of all patients with large choroidal melanomas who have enucleation die from metastases within 5 years of the operation. Therefore, conservative methods such as photocoagulation, irradiation, and microsurgical excision have been used with more or less success to destroy tumor and save a functioning eye.

[Complications of the irradiation therapy with beta applicators in malign melanomas (author's transl)]. / Komplikationen bei der Strahlentherapie des intraokularen Melanoms mit Beta-Applikatoren (106Ru/106Rh).

Depending on prominence and localization of malign melanomas of the choroid, there are - besides enucleation - other clinical treatments possible. Irradiation therapy with beta applicators (106Ru/106Rh) gives also radiogenous complications. But contrarily to a treatment with cobalt-60 applicators, these complications are less important.