However, as in the case of UCN, the major goal in developing these new agents continues to involve disrupting DNA damage checkpoint responses to genotoxic agents or radiation.Whether strategies combining newer checkpoint abrogators and cytotoxic agents will result in improved therapeutic activity or selectivity is currently the subject of intense interest.Nevertheless, numerous clinical trials involving checkpoint abrogators are ongoing based on this rationale.Preclinical data involving LY has not been published.These preclinical data have not yet been published.In vitro, CHIR also potently targets other kinases such as PDGFR. CHIR interacts synergistically with topoisomerase I poisons. In addition, CHIR also sensitizes p HCT cells to IR.CHIR is currently in the preclinical development stage.PD ab rogatesIR induced G M ph ase chec kpo ints and enhances pdependent cell killing. Although much work clearly lies ahead, the future of this field appears promising.The costs of publication of this article were defrayed in part by the payment of page charges.Chk is a histone H threonine kinase that regulates DNA damageinduced transcriptional repression.Access the most recent version of this article at: doi. Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from clincancerres.aacrjournals.org on September. American Association for Cancer Research. Clinical studies have linked the presence of either sulfatereducing bacteria or HS in the colon with chronic disorders such as ulcerative colitis and colorectal cancer, although at this point, the evidence is circumstantial and underlying mechanisms remain undefined.We showed previously that sulfide at concentrations similar to those found in the human colon induced genomic DNA damage in mammalian cells.The present study addressed the nature of the DNA damage by determining if sulfide is directly genotoxic or if genotoxicity requires cellular metabolism.We also questioned if sulfide genotoxicity is mediated by free radicals and if DNA base oxidation is involved.This damage was effectively quenched by cotreatment with butylhydroxyanisole.Furthermore, sulfide treatment increased the number of oxidized bases recognized by formamidopyrimidine DNA glycosylase.These results confirm the genotoxicity of sulfide and strongly implicate that this genotoxicity is mediated by free radicals.The costs of publication of this article were defrayed in part by the payment of page charges.However, an understanding of potential interindividual differences in the density, diversity, and metabolic activity of SRB populations in the human colon is far from complete.Regardless, understanding the effects of HS on the colonic epithelium and the extent of interindividual differences in the responsive pathways is crucial to determine how this intestinal insult may contribute to chronic disorders.Published data indicate that HS can damage the intestinal epithelium, leading to the chronic inflammation, as well as perturb the delicate balance between cellular proliferation and apoptosis, have been extensively studied. Earlier studies on the genotoxicity of HS reported mixed results.SCGE is a sensitive genotoxicity assay and it has a high correlation in predicting carcinogens. The purpose of this research was to determine if HS was a directacting genotoxin and, if so, its mechanism of action and the general type of DNA lesions induced.This objective was motivated by the working hypothesis that at least some forms of sporadic colorectal cancer may represent multifactorial interactions among polymorphic alleles of sulfideresponsive genes and other genes or environmental factors that may influence the density, diversity or metabolic activity of colonic SRB.