Preclinical Pharmacokinetics and Metabolism of MAK683, a Clinical Stage Selective Oral Embryonic Ectoderm Development (EED) Inhibitor for Cancer Treatment

Xenobiotica ◽  
2021 ◽  
pp. 1-48
Author(s):  
Ji Yue (Jeff) Zhang ◽  
Jiangwei Zhang ◽  
Michael Kiffe ◽  
Markus Walles ◽  
Yi Jin ◽  
...  
2019 ◽  
Vol 57 (1) ◽  
pp. 114-121 ◽  
Author(s):  
Yoshinori Handa ◽  
Yasuhiro Tsutani ◽  
Takahiro Mimae ◽  
Yoshihiro Miyata ◽  
Morihito Okada

AbstractOBJECTIVESAlthough segmentectomy for lung cancer has been widely accepted, complex segmentectomy, which creates several, intricate intersegmental planes, remains controversial. Potential arguments include risk of incurability and ‘failure of cancer control’. We compared the outcomes of complex segmentectomy versus lobectomy and evaluated its use in lung cancer treatment.METHODSWe retrospectively reviewed clinical stage IA lung cancer patients who underwent complex segmentectomy (n = 99) or location-adjusted lobectomy (n = 94) between April 2009 and December 2017. Clinicopathological and postoperative results were compared. Factors affecting survival were assessed by the Kaplan–Meier method and the Cox regression analysis.RESULTSNo significant differences were detected in 30-day mortality (0% vs 0%), overall complications (26.3% vs 21.3%) and prolonged air leakage (11.1% vs 9.6%) rates between the 2 groups, respectively. Comparable results were obtained for 5-year overall (93.5% vs 96.4%, respectively; P = 0.21) or recurrence-free (92.3% vs 88.5%, respectively; P = 0.82) survivals after complex segmentectomy or lobectomy. There were 2 (2.0%) recurrences after complex segmentectomy and 7 (7.5%) after lobectomy (P = 0.094), with 0 (0%) margin relapses in each group. Multivariable Cox regression analysis revealed that complex segmentectomy and lobectomy had a numerically similar impact on recurrence-free survival (hazard ratio 0.93, 95% confidence interval 0.32–2.69; P = 0.90).CONCLUSIONSComplex segmentectomy can provide acceptable short- and long-term outcomes in lung cancer treatment.


2015 ◽  
Vol 16 (3) ◽  
pp. 181-186
Author(s):  
Žana Besser Silconi ◽  
Sasa Benazic ◽  
Jelena Milovanovic ◽  
Aleksandar Arsenijevic ◽  
Bojana Stojanovic ◽  
...  

Abstract Since the discovery of the antitumor activity of cisplatin by Rosenberg and co-workers, the use of metal complexes in cancer treatment has caused a huge interest. Today, platinum-based drugs are part of standard chemotherapy in the management of a variety of ca ncers, germ cell tumours, sarcomas, and lymphomas. Unfortunately, toxicity and drug resistance are major obstacles to wider clinical application of these drugs. Their use is greatly limited by severe side effects such as nephrotoxicity, ototoxicity, and neurotoxicity. Although cisplatin is one of the most successful anticancer drugs to date, its biochemical mechanism of action is still unclear. Cisplatin is generally accepted as having the ability to interact with the purine bases on the DNA, causing DNA damage, interfering with DNA repair mechanisms, and subsequently inducing apoptosis in cancer cells. Chronic lymphocytic leukaemia is a neoplastic B cell lymphoproliferative disease characterized by a highly variable clinical course. Clinical stage at the diagnosis and biological prognostic factors are the important predictors for survival. The Rai and Binet staging systems describe three major prognostic subgroups. Commonly used prognostic biomarkers in chronic lymphocytic leukaemia can be divided into genotypic, DNA-level changes and phenotypic, expression-level changes. For chronic lymphocytic leukaemia, substantial progress in therapy has not been made over the past 40 years. The main goal of future scientific research is to find new platinum complexes that have better efficacy in cancer treatment, the ability to be administered orally, without developing a cancer-drug resistance, and reduced toxic side effects.


eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Shanshan Ai ◽  
Yong Peng ◽  
Chen Li ◽  
Fei Gu ◽  
Xianhong Yu ◽  
...  

In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (EedCKO) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in EedCKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized EedCKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.


1998 ◽  
Vol 18 (6) ◽  
pp. 3572-3579 ◽  
Author(s):  
Maarten van Lohuizen ◽  
Marieke Tijms ◽  
Jan Willem Voncken ◽  
Armin Schumacher ◽  
Terry Magnuson ◽  
...  

ABSTRACT The Polycomb group (Pc-G) constitutes an important, functionally conserved group of proteins, required to stably maintain inactive homeobox genes repressed during development. Drosophila extra sex combs (esc) and its mammalian homolog embryonic ectoderm development (eed) are special Pc-G members, in that they are required early during development when Pc-G repression is initiated, a process that is still poorly understood. To get insight in the molecular function of Eed, we searched for Eed-interacting proteins, using the yeast two-hybrid method. Here we describe the specific in vivo binding of Eed to Enx1 and Enx2, two mammalian homologs of the essential DrosophilaPc-G gene Enhancer-of-zeste[E(z)]. No direct biochemical interactions were found between Eed/Enx and a previously characterized mouse Pc-G protein complex, containing several mouse Pc-G proteins includingmouse polyhomeotic (Mph1). This suggests that different Pc-G complexes with distinct functions may exist. However, partial colocalization of Enx1 and Mph1 to subnuclear domains may point to more transient interactions between these complexes, in support of a bridging role for Enx1.


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