Cancer Research UK

About: Cancer Research UK is a nonprofit organization based out in London, United Kingdom. It is known for research contribution in the topics: Cancer & Gene. The organization has 1025 authors who have published 777 publications receiving 148154 citations. The organization is also known as: CRUK.

Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors.

Abstract: Purpose: Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities. Patients and Methods: Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose. Results: Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was dose-limiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (>90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of >6 months was observed in 2 patients. Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.

Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia

Abstract: Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia–carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(–), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v+ metaplastic cells manifested upregulation of xCT expression compared with CD44v− cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT-dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v-xCT could thus prove effective for prevention or attenuation of the CD44v-dependent development of preneoplastic lesions and cancer.

Identification of the E1A-Regulated Transcription Factor p120 E4F as an Interacting Partner of the RASSF1A Candidate Tumor Suppressor Gene

Abstract: Epigenetic inactivation of the candidate tumor suppressor gene RASSF1A is a frequent and critical event in the pathogenesis of many human cancers. The RASSF1A protein contains a Ras association domain, suggesting a role in Ras-like signaling pathways, and has also been implicated in cell cycle progression. However, the preliminary data suggests that the RASSF1A gene product is likely to have multiple functions. To identify novel RASSF1A functions, we have sought to identify interacting proteins by yeast two-hybrid analysis in a human brain cDNA library. We identified the E1A-regulated transcription factor p120(E4F) as a RASSF1A interacting partner in yeast and mammalian cells, and demonstrated that RASSF1A protein and p120(E4F) form a complex in vivo. The interaction between RASSF1A and p120(E4F) was confirmed by both in vitro and in vivo pull downs and coimmunoprecipitation assays. In addition, specific inactivation of RASSF1A by short interfering RNA disrupts binding of RASSF1A to p120(E4F) in coimmunoprecipitation assays. In addition, we demonstrated enhanced G(1) cell cycle arrest and S phase inhibition by propidium iodide staining of p120(E4F) in the presence of RASSF1A. As p120(E4F) has been reported previously to interact with p14ARF, retinoblastoma, and p53, these findings provide an important link between the function of RASSF1A and other major human tumor suppressor genes.

Increasing Human-Organ Transplant Availability: Argumentation-Based Agent Deliberation

Abstract: Human-organ transplantation is the only effective therapy for many life-threatening diseases. However, despite an increase in transplant successes, the lack of a concomitant increase in donor organ availability has led to a growing disparity between supply and demand. Much research has thus focused on defining and implementing policies for increasing donor availability, identifying suitable organ recipients, and documenting transplant procedures. A novel organ-selection process uses a multiagent system called Carrel+ to let geographically dispersed transplant physicians deliberate over organ viability to increase the availability of organs for transplantation

Definition of a short region of XPG necessary for TFIIH interaction and stable recruitment to sites of UV damage.

Abstract: XPG is the human endonuclease that cuts 3′ to DNA lesions during nucleotide excision repair. Missense mutations in XPG can lead to xeroderma pigmentosum (XP), whereas truncated or unstable XPG proteins cause Cockayne syndrome (CS), normally yielding life spans of <7 years. One XP-G individual who had advanced XP/CS symptoms at 28 years has been identified. The genetic, biochemical, and cellular defects in this remarkable case provide insight into the onset of XP and CS, and they reveal a previously unrecognized property of XPG. Both of this individual's XPG alleles produce a severely truncated protein, but an infrequent alternative splice generates an XPG protein lacking seven internal amino acids, which can account for his very slight cellular UV resistance. Deletion of XPG amino acids 225 to 231 does not abolish structure-specific endonuclease activity. Instead, this region is essential for interaction with TFIIH and for the stable recruitment of XPG to sites of local UV damage after the prior recruitment of TFIIH. These results define a new functional domain of XPG, and they demonstrate that recruitment of DNA repair proteins to sites of damage does not necessarily lead to productive repair reactions. This observation has potential implications that extend beyond nucleotide excision repair.