Pregled lijekova protiv raka koji ciljano djeluju na mikrotubule

The entire world is looking for effective cancer therapies whose benefits would outweigh their toxicity. One way to reduce resistance to chemotherapy and its adverse effects is the so called targeted therapy, which targets specific molecules (“molecular targets”) that play a critical role in cancer growth, progression, and metastasis. One such specific target are microtubules. In this review we address the current knowledge about microtubule-targeting agents or drugs (MTAs/MTDs) used in cancer therapy from their synthesis to toxicities. Synthetic and natural MTAs exhibit antitumor activity, and preclinical and clinical studies have shown that their anticancer effectiveness is higher than that of traditional drug therapies. Furthermore, MTAs involve a lower risk of adverse effects such as neurotoxicity and haemotoxicity. Several new generation MTAs are currently being evaluated for clinical use. This review brings updated information on the benefits of MTAs, therapeutic approaches, advantages, and challenges in their research.U cijelome se svijetu traga za djelotvornim liječenjem protiv raka čije bi koristi prevagnule nad štetnim djelovanjem. Jedan od načina da se smanji otpornost na kemoterapiju i njezine štetne učinke svakako je takozvano ciljano liječenje, usmjereno na pojedine molekule (molekulske ciljeve) koje imaju važnu ulogu u rastu, napredovanju i metastaziranju raka. Primjer takvih specifičnih ciljeva su mikrotubuli. U ovom se preglednom radu osvrćemo na najnovije spoznaje o lijekovima koji ciljano djeluju na mikrotubule (engl. microtubule-targeting agents/drugs, krat. MTA/MTD), a rabe se u liječenju raka. Takvi prirodni i sintetizirani lijekovi djeluju protutumorski, a pretklinička istraživanja i klinička ispitivanja pokazuju da je njihova djelotvornost veća nego ona tradicionalnih lijekova. Osim toga, ti lijekovi donose manji rizik od štetnih učinaka poput neurotoksičnosti i hemotoksičnosti. Upravo se klinički ocjenjuju nove generacije nekoliko lijekova koji ciljano djeluju na mikrotubule. Ovdje donosimo najnovije spoznaje o njihovim koristima, pristupima liječenju, prednostima i izazovima u istraživanju

Degradation of azo dyes by sequential Fenton's oxidation and aerobic biological treatment

A two stage sequential Fenton's oxidation followed by aerobic biological treatment train was used to achieve decolorization and to enhance mineralization of azo dyes, viz. Reactive Black 5 (RB5), Reactive Blue 13 (RB13), and Acid Orange 7 (AO7). In the first stage, Fenton's oxidation process was used while in the second stage aerobic sequential batch reactors (SBRs) were used as biological process. Study was done to evaluate effect of pH on Fenton's oxidation process. Results reveal that pH 3 was optimum pH for achieving decolorization and dearomatization of dyes by Fenton's process. Degradation of dye was assessed by COD reduction and reduction in aromatic amines (naphthalene chromophores) which was measured by reduction in absorbance at 200 nm. More than 95% of color was removed with Fenton's oxidation process in all dyes. In overall treatment train 81.95, 85.57, and 77.83% of COD reduction was achieved in RB5, RB13, and AO7 dyes, respectively. In the Fenton's oxidation process 56, 24.5, and 80% reduction in naphthalene group was observed in RB5, RB13, and AO7, respectively, which further increased to 81.34, 68.73, and 92% after aerobic treatment. Fenton's oxidation process followed by aerobic SBRs treatment sequence seems to be viable method for achieving significant degradation of azo dye.© Elsevie

Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome

Snyder Robinson Syndrome (SRS) is a rare disease associated with a defective spermine synthase gene and low intracellular spermine levels. In this study, a spermine replacement therapy was developed using a spermine prodrug that enters cells via the polyamine transport system. The prodrug was comprised of three components: a redox-sensitive quinone “trigger”, a “trimethyl lock (TML)” aryl “release mechanism”, and spermine. The presence of spermine in the design facilitated uptake by the polyamine transport system. The quinone–TML motifs provided a redox-sensitive agent, which upon intracellular reduction generated a hydroquinone, which underwent intramolecular cyclization to release free spermine and a lactone byproduct. Rewardingly, most SRS fibroblasts treated with the prodrug revealed a significant increase in intracellular spermine. Administering the spermine prodrug through feeding in a Drosophila model of SRS showed significant beneficial effects. In summary, a spermine prodrug is developed and provides a lead compound for future spermine replacement therapy experiments

Primary Leiomyosarcoma of the Gallbladder

Leiomyosarcoma (LMS) of the gallbladder is an extremely rare entity. Most reported cases were mistakenly diagnosed preoperatively as cholecystitis with or without cholelithiasis. We believe that our article demonstrates the 5th case of gallbladder LMS that was suspected preoperatively to be malignant rather than cholecystitis, which fortunately led to radical resection of the tumor instead of simple cholecystectomy. However, the definitive diagnosis relies exclusively on histological and immunohistochemical techniques. We present a case of a 62-year-old Caucasian female complaining of signs and symptoms suggestive for cholecystitis. On ultrasonography, the gallbladder appeared enlarged and filled with a necrotic mass; thus, the presence of adenocarcinoma was suspected. Multislice Computerized Tomography (MSCT) demonstrated no distant metastasis. An extensive radical cholecystectomy was performed, and histological techniques confirmed a leiomyosarcoma diagnosis. In addition, adjuvant chemotherapy of doxorubicin and ifosfamide was administrated. The patient was on follow-up for 2 years and is doing well till date. The discrimination of gallbladder sarcoma preoperatively remains a clinical and radiological challenge. Although radical resection of the tumor remains the mainstay of the treatment, we believe that adjuvant chemotherapy should be administrated in such cases. However, further studies are required in this field

Docking of NMK-TD-100 to tubulin.

<p>(<b>A</b>) <i>In </i><i>silico</i> binding of NMK-TD-100 (yellow) on tubulin heterodimers. In the ribbon diagram grey represents α-tubulin monomer and blue represents β-tubulin monomer. (<b>B</b>) 3D diagram representing binding site of NMK-TD-100 on tubulin heterodimers. Red is showing the polar domains, blue stands for non-polar domains and white stands for neutral domains on protein surface. (<b>C</b>) Ball and stick figure showing positions of hydrogen bonds which stabilizes NMK-TD-100 molecule on protein surface. (<b>D</b>) The crystal structure of αβ heterodimer of tubulin depicting the proximity of the binding sites for colchicine (yellow) and NMK-TD-100 (red).</p

Binding of NMK-TD-100 to tubulin as assessed by enhancement of ligand fluorescence.

<p>(<b>A</b>) Fluorescence emission spectra of NMK-TD-100 (2 µM) in buffer (curve a) and in the presence of 2 (curve b), 5 (curve c), 7.5 (curve d), 10 (curve e) and 15 (curve f) µM of tubulin. (<b>B</b>) Fluorescence emission spectra of NMK-TD-100 (20 µM) in the presence of aqueous buffer (PEM buffer) and methanol. (<b>C</b>) Scatchard Plot of NMK-TD-100 binding to tubulin. (<b>D</b>) Job Plot for binding of NMK-TD-100 to tubulin. The concentrations of NMK-TD-100 and tubulin were varied continuously whereas the total concentration of tubulin and NMK-TD-100 was kept fixed at 5 µM. The corrected fluorescence value at 450 nm was plotted against the mole fraction of NMK-TD-100. The excitation and emission wavelengths were 340 and 450nm respectively for all the above panels. Data are representative of three similar experiments. Details of all the experiments are described in the ‘Materials and methods’ section.</p