Growth inhibition of human ovarian carcinoma by a novel AvidinOX-anchored biotinylated camptothecin derivative

Oxidized form of avidin, named AvidinOX, provides stable fixation of biotinylated molecules in tissues thus representing a breakthrough in topical treatment of cancer. AvidinOX proved to be a stable receptor for radiolabeled biotin, biotinylated antibodies and cells. In order to expand applicability of the AvidinOX-based delivery platform, in the present study we investigated the possibility to hold biotinylated chemotherapeutics in AvidinOX-treated sites. A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX. Significantly higher growth inhibition was observed when the drug was anchored to AvidinOX suggesting the potential utility of this delivery modality for the local treatment of inoperable tumors

Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors

A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation

7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors

7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals

The protease‐activated receptor 4 Ala120Thr variant alters platelet responsiveness to low‐dose thrombin and protease‐activated receptor 4 desensitization, and is blocked by non‐competitive P2Y12 inhibition

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146616/1/jth14318_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146616/2/jth14318.pd

metabolic approach to the enhancement of antitumor effect of chemotherapy a key role of acetyl l carnitine

Purpose: Acetyl-l-carnitine (ALC) plays a relevant role in energy metabolism and stress response because of its function in the complex metabolic system regulating the acetyl-CoA levels that provide a source of acetyl groups for metabolic and acetylation-regulated processes. Because acetylation may influence p53 activity/stability and, therefore, the response to platinum compounds, this study was designed to investigate the effect of ALC in combination with platinum compounds. Experimental Design: The antiproliferative and antitumor activity studies were done in a panel of human tumor cell lines with functional or defective p53. The antimetastatic drug efficacy was investigated in the s.c. growing H460/M tumor subline, which is able to generate lung metastases. Results: ALC enhanced the sensitivity to cisplatin of tumor cells with functional p53. The sensitization by ALC was reflected in an improved in vivo antitumor efficacy of the combination over cisplatin alone in wild-type p53 lung tumors. ALC did not increase the cisplatin efficacy in the p53-mutant SW620 tumor. ALC exhibited a significant antimetastatic activity, and this effect was better exploited in combination with the histone deacetylase inhibitor, ST3595. The in vivo ALC/cisplatin combination caused the activation of p53, associated with protein acetylation and induction of target genes. Conclusions: ALC was effective in enhancing the antitumor potential of platinum compounds in wild-type p53 tumors. ALC, alone and in combination with a histone deacetylase inhibitor, exhibited an outstanding antimetastatic activity. Both effects, likely mediated by protein acetylation, may have implications for platinum-based therapy and combinations with histone deacetylase inhibitors. Clin Cancer Res; 16(15); 3944–53. ©2010 AACR

Characterization of Early and Late Damage in a Mouse Model of Pelvic Radiation Disease

Pelvic radiation disease (PRD), a frequent side effect in patients with abdominal/pelvic cancers treated with radiotherapy, remains an unmet medical need. Currently available preclinical models have limited applications for the investigation of PRD pathogenesis and possible therapeutic strategies. In order to select the most effective irradiation protocol for PRD induction in mice, we evaluated the efficacy of three different locally and fractionated X-ray exposures. Using the selected protocol (10 Gy/day x 4 days), we assessed PRD through tissue (number and length of colon crypts) and molecular (expression of genes involved in oxidative stress, cell damage, inflammation, and stem cell markers) analyses at short (3 h or 3 days after X-ray) and long (38 days after X-rays) post-irradiation times. The results show that a primary damage response in term of apoptosis, inflammation, and surrogate markers of oxidative stress was found, thus determining a consequent impairment of cell crypts differentiation and proliferation as well as a local inflammation and a bacterial translocation to mesenteric lymph nodes after several weeks post-irradiation. Changes were also found in microbiota composition, particularly in the relative abundance of dominant phyla, related families, and in alpha diversity indices, as an indication of dysbiotic conditions induced by irradiation. Fecal markers of intestinal inflammation, measured during the experimental timeline, identified lactoferrin, along with elastase, as useful non-invasive tools to monitor disease progression. Thus, our preclinical model may be useful to develop new therapeutic strategies for PRD treatment

Synthesis and evaluation of new Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold

Abstract: Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates, gave a new family of 1,4,5-trisubstitued triazole carboxylic acid derivatives that showed high affinity towards Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring, were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstitued triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18; SST0287CL1) was selected for further investigation as the most promising drug candidate

Predatory Behavior and Web Orientation of the Golden Orb-Weaving Spider, Nephila Clavipes Linnaeus

Nephila clavipes is a type of orb-weaving spider. This means that their web comprises a hub, radii, and a sticky spiral in an orb shape. Orb weavers typically have poor vision and feel vibrations in their web to detect prey. Nephila clavipes is mostly found in the southern U.S. and in tropical climates. Adult female Nephila webs are usually very large, averaging 1 m (39’’) or more in diameter. These spiders are not poisonous to humans but may seem intimidating because of the large size of the female, which varies but is about 25 mm (1”) body length. The purpose of this study was to describe their predatory behavior and web orientation. Searches were conducted in Tree Tops Park and because of their size they were spotted fairly quickly along nature paths. The date, time, location, temperature, and weather were noted first. The first measurements were done at a distance and include measuring the angle of the plane of the web with a clinometer, noting missing legs, measuring the compass direction of the dorsum, noting wrapped prey, barrier webs, Argyrodes (kleptoparasitic spiders), male Nephila, and any damage to their web. The next measurement was touching a 100Hz tuning fork to the web to simulate prey. Responses were scored 0-6 (no response to full response). Leg segments were measured as an index of size of the spider, along with how high the hub of the web was from the ground, the spiral height, and the spiral width. The results found theNephila clavipes typically have webs that face east. Their webs were found to be only slightly inclined from vertical. The response to the 100Hz tuning fork usually was an approach and bite of the fork. The tendency of the spiders to build their webs facing east may be related to thermoregulation or prey capture. The response to the 100Hz tuning fork closely resembles the Nephila response to relatively small, nonthreatening prey

Caffeine effects on the predatory behavior of the orb-weaving spider, Argiope argentata

Argiope argentata are orb-weaving spiders--meaning that their webs are a sticky spiral wound around radii extending from a central hub. A. argentata have poor vision and depend on vibrations in their web for detection of prey. A. argentata are large spiders; the female is 25mm and the male is 10 mm. They build webs that are approximately 80cm across. Research thus far on spiders and drugs have focused on web-building behavior after depressants or hallucinatory substances have been administered. Research on stimulants and predatory behavior has not been addressed. The proposed research is an exploratory study investigating the effects of stimulants on predatory behavior in A.argentata. This study will be a between-subjects experiment with two groups. A control group will be used for baseline measures of predatory behavior. An experimental group will be administered caffeine prior to the measurements of predatory behavior. A prey item is simulated by use of a 100 Hz tuning fork. The fork is struck and the tine is placed in the web to create a vibration. Responses are scored from no response to full response. A full response score is given if the spider approaches the fork as they would a prey item. It is unknown what effect the caffeine will have on predatory behavior