Y 134

Sustained safety and efficacy of extended-shelf-life (90)Y glass microspheres: long-term follow-up in a 134-patient cohort.[Pubmed:24114004]

Eur J Nucl Med Mol Imaging. 2014 Mar;41(3):486-93.

PURPOSE: To validate our initial pilot study and confirm sustained safety and tumor response of extended-shelf-life (90)Y glass microspheres. We hypothesized that for the same planned tissue dose, the increase in number of glass microspheres (decayed to the second week of their allowable shelf-life) administered for the same absorbed dose would result in better tumor distribution of the microspheres without causing additional adverse events. METHODS: Between June 2007 and January 2010, 134 patients underwent radioembolization with extended-shelf-life (90)Y glass microspheres; data from 84 new patients were combined with data from our 50-patient pilot study cohort. Baseline and follow-up imaging and laboratory data were obtained 1 and 3 months after therapy and every 3 months thereafter. Clinical and biochemical toxicities were prospectively captured and categorized according to the Common Terminology Criteria. Response in the index lesion was assessed using WHO and EASL guidelines. RESULTS: The mean delivered radiation dose was 123 Gy to the target liver tissue. The mean increase in number of microspheres with this approach compared to standard (90)Y glass microsphere dosimetry was 103%, corresponding to an increase from 3.84 to 7.78 million microspheres. Clinical toxicities included fatigue (89 patients, 66%), abdominal pain (49 patients, 36.6%), and nausea/vomiting (25 patients, 18.7%). Grade 3/4 bilirubin toxicity was seen in three patients (2%). Two (1%) of the initial 50-patient cohort showed gastroduodenal ulcers; gastroduodenal ulcers were not seen in any of the subsequent 84 patients. According to WHO and EASL guidelines, response rates were 48% and 57%, respectively, and 21% demonstrated a complete EASL response. CONCLUSION: This study showed sustained safety and efficacy of extended-shelf-life (90)Y glass microspheres in a larger, 134-patient cohort. The increase in number of microspheres administered theoretically resulted in better tumor distribution of the microspheres without an increase in adverse events.

The second cholesterol oxidase produced by gamma-proteobacterium Y-134.[Pubmed:16233518]

J Biosci Bioeng. 2003;96(3):257-61.

A new strain, Y-134, which was isolated as a producer of cholesterol oxidase (CHO) with high stability in detergents, produced two cholesterol oxidases; one (CHO-A) adsorbed to DEAE-Sepharose, while the other (CHO-U) did not. Specific properties of purified CHO-U were compared with those of CHO-A [Isobe et al., J. Biosci. Bioeng., 95, 257-263 (2003)]. The amino acid sequences of 30 residues from the NH2 terminus were identical in both enzymes, except for one unascertained residue. CHO-U was also stable in nonionic detergents. However, many other properties of CHO-U were different from those of CHO-A; The purified CHO-U exhibited an absorption spectrum characteristic of a flavoprotein with absorption maxima at 276, 350, and 450 nm, and the enzyme activity was not enhanced by metals. CHO-U was a monomeric enzyme with 58 kDa of molecular mass and pI of 7.0. The optimum pH of CHO-U was more than 0.5 acidic pH in relation to that of CHO-A, but the stability of alkaline pH was higher than CHO-A. In addition, the K(m) value for cholesterol was lower than that of CHO-A, and the V(max) value was higher.

Biological activities of a novel selective oestrogen receptor modulator derived from raloxifene (Y134).[Pubmed:17115070]

Br J Pharmacol. 2007 Jan;150(1):19-28.

BACKGROUND AND PURPOSE: Selective oestrogen receptor (ER) modulators (SERMs) are of great value in the treatment of breast cancer and osteoporosis. The aim of this study was to characterize pharmacologically a new class of SERMs synthesized based on the core structure of raloxifene. EXPERIMENTAL APPROACH: Competitive receptor binding and luciferase-based reporter methods were used to study the bioactivities of raloxifene analogues, followed by efficacy determination in breast cancer cell proliferation assay. ER antagonist effects were investigated in female rats by measuring uterine and mammary gland growth, using wet weight, BrdU incorporation and terminal end bud (TEB) as indicators. KEY RESULTS: Five analogues, belonging to two different structural series and display higher binding affinities for ERalpha than ERbeta were functionally evaluated. One such analogue, Y134, exhibited potent antagonist activity at ERs in CV-1 cells cotransfected with plasmids containing ERalpha or ERbeta and oestrogen-response element-driven luciferase. The estimated IC(50) value was 0.52 nM for ERalpha and 2.94 nM for ERbeta, comparable to that of raloxifene. Little cytotoxicity was observed at Y134 concentrations below 10 microM. Y134 suppressed oestrogen-stimulated proliferation of ER-positive human breast cancer MCF-7 and T47D cells. At an identical dose, administered to ovariectomized rats, Y134 was more effective than raloxifene at arresting oestrogen-induced outgrowth of TEB and mammary gland DNA synthesis, but their inhibitory effects on the uterus were comparable. CONCLUSIONS AND IMPLICATIONS: Y134 is a potent ER antagonist with better mammary gland selectivity than raloxifene and shows potential for development as a new SERM for therapeutic use.

Benzothiophenes containing a piperazine side chain as selective ligands for the estrogen receptor alpha and their bioactivities in vivo.[Pubmed:15713417]

Bioorg Med Chem Lett. 2005 Mar 1;15(5):1505-7.

The synthesis of benzothiophenes containing a piperazine side chain and their binding affinities for estrogen receptors are described. These compounds bearing piperazine side chains were identified to be high-affinity ligands with high selectivity for ER alpha subtype. They were also potent agonists in bone tissue.