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1.
Mol Cancer Ther ; 20(6): 975-985, 2021 06.
Article in English | MEDLINE | ID: mdl-33722854

ABSTRACT

KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non-small cell lung cancer (NSCLC). PD-1 inhibitors are approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) are needed. KRASG12C mutations are smoking-associated transversion mutations associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive tumor microenvironment. To evaluate the potential of MRTX849 to augment CIT, its impact on immune signaling and response to CIT was evaluated. In human tumor xenograft models, MRTX849 increased MHC class I protein expression and decreased RNA and/or plasma protein levels of immunosuppressive factors. In a KrasG12C -mutant CT26 syngeneic mouse model, MRTX849 decreased intratumoral myeloid-derived suppressor cells and increased M1-polarized macrophages, dendritic cells, CD4+, and CD8+ T cells. Similar results were observed in lung KrasG12C -mutant syngeneic and a genetically engineered mouse (GEM) model. In the CT26 KrasG12C model, MRTX849 demonstrated marked tumor regression when tumors were established in immune-competent BALB/c mice; however, the effect was diminished when tumors were grown in T-cell-deficient nu/nu mice. Tumors progressed following anti-PD-1 or MRTX849 single-agent treatment in immune-competent mice; however, combination treatment demonstrated durable, complete responses (CRs). Tumors did not reestablish in the same mice that exhibited durable CRs when rechallenged with tumor cell inoculum, demonstrating these mice developed adaptive antitumor immunity. In a GEM model, treatment with MRTX849 plus anti-PD-1 led to increased progression-free survival compared with either single agent alone. These data demonstrate KRAS inhibition reverses an immunosuppressive tumor microenvironment and sensitizes tumors to CIT through multiple mechanisms.


Subject(s)
Acetonitriles/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Piperazines/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Pyrimidines/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Disease Models, Animal , Humans , Immune Checkpoint Inhibitors/pharmacology , Mice , Tumor Microenvironment/drug effects
2.
Pharmacol Res ; 47(6): 509-15, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12742004

ABSTRACT

Dibromoacetonitrile (DBAN) is known to be water disinfectant by-product. Its broad-spectrum toxicity in different test systems in vivo and in vitro has been reported. Oxidative damage induced by DBAN may be partially responsible for its toxicity. Herein, the ability of DBAN to induce oxidative stress in mouse testis and possible protective effect of an antioxidant tertiary butylhydroquinone (TBHQ) were addressed. Male albino mice were injected with a single dose of DBAN (50mg/kg i.p.), and killed after 3h of treatment. Control animals received 10ml/kg body weight i.p. of the vehicle DMSO. In both experiments, cauda epididymis were dissected and sperm count and motility were investigated. Also, testicular activity of lactic dehydrogenase-x (LDH-x) isozyme and histopathological changes were examined. Furthermore, testicular content of malonyldialdehyde (MDA) and reduced glutathione (GSH) were determined. A single i.p. dose of DBAN caused decrease in sperm count and motility to approximately 88 and 84%, respectively, compared with control animals. A 46% decrease in testicular activity of LDH-x, compared with control animals, was observed. A significant accumulation of MDA in DBAN-treated animals was increased to 99% while testicular content of GSH was decreased by 56% compared to control animals. Compared to DBAN-treated animals, treatment with TBHQ (100mg/kg p.o.) prior exposure to DBAN showed a remarkable degree of protection as indicated by enhancement of sperm count and motility, testicular activity of LDH-x, and GSH. Accumulation of testicular content of MDA significantly decreased following TBHQ treatment compared to DBAN-treated animals. In conclusion, results presented here indicate that DBAN is capable to induce oxidative stress in mouse testis. TBHQ may play a protective role against DBAN-induced testicular cellular damage.


Subject(s)
Acetonitriles/antagonists & inhibitors , Acetonitriles/toxicity , Hydroquinones/pharmacology , Testis/drug effects , Analysis of Variance , Animals , Glutathione/metabolism , Isoenzymes/metabolism , L-Lactate Dehydrogenase/metabolism , Male , Malondialdehyde/metabolism , Mice , Oxidative Stress/drug effects , Sperm Count , Sperm Motility , Testis/metabolism , Testis/pathology
3.
Protein Eng ; 14(1): 47-59, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11287678

ABSTRACT

Multiple Solvent Crystal Structures (MSCS) is a crystallographic technique to identify energetically favorable positions and orientations of small organic molecules on the surface of proteins. We determined the high-resolution crystal structures of thermolysin (TLN), generated from crystals soaked in 50--70% acetone, 50--80% acetonitrile and 50 mM phenol. The structures of the protein in the aqueous-organic mixtures are essentially the same as the native enzyme and a number of solvent interaction sites were identified. The distribution of probe molecules shows clusters in the main specificity pocket of the active site and a buried subsite. Within the active site, we compared the experimentally determined solvent positions with predictions from two computational functional group mapping techniques, GRID and Multiple Copy Simultaneous Search (MCSS). The experimentally determined small molecule positions are consistent with the structures of known protein--ligand complexes of TLN.


Subject(s)
Thermolysin/chemistry , Acetone/antagonists & inhibitors , Acetonitriles/antagonists & inhibitors , Binding Sites , Computer-Aided Design , Crystallography, X-Ray , Drug Design , Hydrogen Bonding , Ligands , Models, Molecular , Molecular Structure , Phenol/antagonists & inhibitors , Protease Inhibitors/chemistry , Protein Binding , Protein Conformation , Protein Structure, Secondary , Solvents , Static Electricity , Thermodynamics , Water/chemistry
4.
J Toxicol Environ Health ; 15(5): 609-21, 1985.
Article in English | MEDLINE | ID: mdl-4046068

ABSTRACT

The purpose of these studies was to investigate the nature and mechanism of a toxicologic interaction between acetonitrile and acetone. Results of oral dose-response studies utilizing a 1:1 (w/w) mixture of acetonitrile and acetone, or varying doses of acetonitrile administered together with a constant dose of acetone, indicated that acetone potentiated acute acetonitrile toxicity three- to fourfold in rats. The onset of severe toxicity (manifested by tremors and convulsions) was delayed in the groups dosed with both solvents compared to the groups that received acetonitrile or acetone alone. Blood cyanide (a metabolite of acetonitrile) and serum acetonitrile and acetone concentrations were measured after oral administration of 25% aqueous solutions of acetonitrile, acetone, or acetonitrile plus acetone. Concentrations of cyanide in the blood of rats given acetonitrile plus acetone remained near baseline, in contrast to the high concentrations found in rats dosed with acetonitrile alone. At 34-36 h, high blood cyanide concentrations were found in rats dosed with both of the solvents. This delayed onset of elevation of blood cyanide coincided with the occurrence of clinical signs and with the disappearance of serum acetone. In further pharmacokinetic studies, blood cyanide concentrations were measured after similar dosage regimens of acetone and acetonitrile. Peak cyanide concentrations were found to be significantly greater in rats dosed with both solvents than in rats given only acetonitrile. Administration of either sodium thiosulfate or a second dose of acetone prevented the toxicity associated with exposure to both solvents. These results suggest that the effects of acetone on acetonitrile toxicity are due to a biphasic effect on the metabolism of acetonitrile to cyanide, that is, an initial inhibition followed by a stimulation of this metabolism upon acetone elimination.


Subject(s)
Acetone/toxicity , Acetonitriles/toxicity , Acetone/antagonists & inhibitors , Acetone/blood , Acetonitriles/antagonists & inhibitors , Acetonitriles/blood , Animals , Cyanides/blood , Dose-Response Relationship, Drug , Drug Synergism , Female , Kinetics , Lethal Dose 50 , Rats , Rats, Inbred Strains , Seizures/chemically induced , Thiosulfates/pharmacology , Tremor/chemically induced
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