ABSTRACT
Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.
Subject(s)
Cyclin-Dependent Kinase 4/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Naphthyridines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Nude , Naphthyridines/pharmacokinetics , Naphthyridines/therapeutic use , Neoplasms, Experimental , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Phenylurea Compounds/pharmacology , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/pharmacology , Signal Transduction/drug effects , Sorafenib , U937 Cells , Xenograft Model Antitumor AssaysABSTRACT
The RXopJ4 resistance locus from the wild accession Solanum pennellii (Sp) LA716 confers resistance to bacterial spot disease of tomato (S. lycopersicum, Sl) caused by Xanthomonas perforans (Xp). RXopJ4 resistance depends on recognition of the pathogen type III effector protein XopJ4. We used a collection of Sp introgression lines (ILs) to narrow the RXopJ4 locus to a 4.2-Mb segment on the long arm of chromosome 6, encompassed by the ILs 6-2 and 6-2-2. We then adapted or developed a collection of 14 molecular markers to map on a segregating F(2) population from a cross between the susceptible parent Sl FL8000 and the resistant parent RXopJ4 8000 OC(7). In the F(2) population, a 190-kb segment between the markers J350 and J352 cosegregated with resistance. This fine mapping will enable both the identification of candidate genes and the detection of resistant plants using cosegregating markers. The RXopJ4 resistance gene(s), in combination with other recently characterized genes and a quantitative trait locus (QTL) for bacterial spot disease resistance, will likely be an effective tool for the development of durable resistance in cultivated tomato.
Subject(s)
Chromosome Mapping , Disease Resistance/genetics , Plant Diseases/genetics , Quantitative Trait Loci , Solanum/genetics , Chromosomes, Plant , DNA, Plant/genetics , Genes, Plant , Genetic Markers , Phenotype , Plant Diseases/microbiology , Sequence Analysis, DNA , Solanum/microbiology , Xanthomonas/isolation & purificationABSTRACT
A phosphorus solubilizing bacterium, designated phosphobacterium 9320-SD, was isolated from field soil in Tianjin, China. Cells of the phosphobacterium 9320-SD were gram-positive, rod shaped, and produced spores. When 9320-SD was inoculated into MPMLM, amended with powdered (insoluble) mineral phosphate as the single P source, and incubated at 30 degrees C, the release of soluble phosphorus increased with increasing amounts of added phosphates over the range of 0.12-4% (w/v). The maximal available phosphorus reached 12.01 mmol P/L after 7 days incubation. Furthermore, there was a direct positive correlation (r = 0.9330) between the level of soluble phosphorus release and the concentration of viable bacteria. SEM study of the phosphate powder retrieved from the phosphobacterium 9320-SD cultured medium revealed the actual dissolution of phosphate from the mineral surface. Phosphobacterium 9320-SD had significant effect (p < 0.05) on winter wheat total P and plant biomass under both pot and field conditions, although no obvious difference in plant height was found compared to the control. Taken together, these results demonstrate that phosphobacterium 9320-SD has the ability to convert non-available forms of phosphorus into plant-available forms, and therefore holds great potential for development as a biofertilizer to enhance soil fertility and promote plant growth.