• Deuterium isotope effect
• Metabolism
• Pharmacokinetics
• Sorafenib
• [14C]-donafenib

• Humans
• Male
• Adult
• Administration, Oral
• Carbon Radioisotopes
• Feces/chemistry
• Pyridines/pharmacokinetics
• Pyridines/administration & dosage
• Young Adult
• Healthy Volunteers
• Antineoplastic Agents/pharmacokinetics
• Antineoplastic Agents/administration & dosage
• Liver/metabolism
• Liver/drug effects

• BE2021644 Jiangsu Provincial Key Research and Development Program
• QNRC2016714 Jiangsu Provincial Medical Youth Talent
• GSWS2019001 Suzhou Health Leading Talent

The molecular consequences of cancer associated mutations in Acute myeloid leukemia (AML) linked factors are not very well understood. Here, we interrogated the COSMIC database for missense mutations associated with the RUNX1 protein, that is frequently mis-regulated in AML, where we sought to identify recurrently mutated positions at the DNA-interacting interface. Indeed, six of the mutated residues, out of a total 417 residues examined within the DNA binding domain, evidenced reduced DNA association in in silico predictions. Further, given the prominence of RUNX1’s compromised function in AML, we asked the question if the mutations themselves might alter RUNX1’s interaction (off-target) with known FDA-approved drug molecules, including three currently used in treating AML. We identified several AML-associated mutations in RUNX1 that were calculated to enhance RUNX1’s interaction with specific drugs. Specifically, we retrieved data from the COSMIC database for cancer-associated mutations of RUNX1 by using R package “data.table” and “ggplot2” modules. In the presence of DNA and/or drug, we used docking scores and energetics of the complexes as tools to evaluate predicted interaction strengths with RUNX1. For example, we performed predictions of drug binding pockets involving Enasidenib, Giltertinib, and Midostaurin (AML associated), as well as ten different published cancer associated drug compounds. Docking of wild type RUNX1 with these 13 different cancer-associated drugs indicates that wild-type RUNX1 has a lower efficiency of binding while RUNX1 mutants R142K, D171N, R174Q, P176H, and R177Q suggested higher affinity of drug association. Literature evidence support our prediction and suggests the mutation R174Q affects RUNX1 DNA binding and could lead to compromised function. We conclude that specific RUNX1 mutations that lessen DNA binding facilitate the binding of a number of tested drug molecules. Further, we propose that molecular modeling and docking studies for RUNX1 in the presence of DNA and/or drugs enables evaluation of the potential impact of RUNX1 cancer associated mutations in AML.

The relationships between drug pharmacodynamics and subsequent changes in cellular signaling processes are complex. Many in vitro cell signaling studies often use drug concentrations above physiologically safe drug levels achievable in a patient's plasma. Drug companies develop agents to inhibit or modify the activities of specific target enzymes, often without a full consideration that their compounds have additional unknown targets. These two negative sequelae, when published together, become impediments against successful developmental therapeutics and translation because this data distorts our understanding of signaling mechanisms and reduces the probability of successfully translating drug-based concepts from the bench to the bedside. This article will discuss cellular signaling in isolation and as it relates to extant single and combined therapeutic drug interventions. This will lead to a hypothetical series standardized sequential approaches describing a rigorous concept to drug development and clinical translation.

• ATG13
• ERK1/2
• FIP200
• autophagy
• hypoglycemia
• renal cells

Objective: To evaluate different targeted anticancer agents for patients with advanced or unresectable hepatocellular carcinoma (HCC) based on network meta-analysis.

Methods: Literature retrieval was conducted in globally recognized databases, namely, MEDLINE, PMC, EMBASE and Cochrane Central to find relevant randomized controlled trials (RCTs). Relative parametric data, including overall survival (OS), progression-free survival (PFS) and adverse event (AE), were quantitatively pooled and estimated based on the Bayesian theorem. The values of the surface under the cumulative ranking (SUCRA) probabilities regarding each parameter were calculated and ranked. Node-splitting analysis was performed to test the inconsistency of the main results, and publication bias was assessed by examining funnel-plot symmetry.

Results: After a detailed review, 31 RCTs containing 20 different agents or combinations were finally included for network meta-analysis. For patients without previously systematic treatments, lenvatinib had the best clinical effects on OS (SUCRA, 0.22), and apatinib was superior regarding PFS (SUCRA, 0.41) and AE (SUCRA, 0.15). For patients who received previously targeted agents therapies, regorafenib exhibited the superior clinical effects on OS (SUCRA, 0.42) and PFS (SUCRA, 0.30), while codrituzumab showed the greatest safety benefit on AE (SUCRA, 0.75). Moreover, node-splitting analysis and funnel-plot symmetries illustrated no inconsistency or obvious publication bias in the current study.

Conclusions: According to current evidence, lenvatinib and apatinib had superior clinical effects for patients without previously systematic treatments, and regorafenib seemed to be more suitable for patients with previously targeted agent therapies. However, our conclusions still need more statistical validations, and more high-quality trials are expected.

• hepatocellular carcinoma
• network meta-analysis
• targeted agent

Influenza viruses (IVs) tend to rapidly develop resistance to virus-directed vaccines and common antivirals targeting pathogen determinants, but novel host-directed approaches might preclude resistance development. To identify the most promising cellular targets for a host-directed approach against influenza, we performed a comparative small interfering RNA (siRNA) loss-of-function screen of IV replication in A549 cells. Analysis of four different IV strains including a highly pathogenic avian H5N1 strain, an influenza B virus (IBV) and two human influenza A viruses (IAVs) revealed 133 genes required by all four IV strains. According to gene enrichment analyses, these strain-independent host genes were particularly enriched for nucleocytoplasmic trafficking. In addition, 360 strain-specific genes were identified with distinct patterns of usage for IAVs versus IBV and human versus avian IVs. The strain-independent host genes served to define 43 experimental and otherwise clinically approved drugs, targeting reportedly fourteen of the encoded host factors. Amongst the approved drugs, the urea-based kinase inhibitors (UBKIs) regorafenib and sorafenib exhibited a superior therapeutic window of high IV antiviral activity and low cytotoxicity. Both UBKIs appeared to block a cell signaling pathway involved in IV replication after internalization, yet prior to vRNP uncoating. Interestingly, both compounds were active also against unrelated viruses including cowpox virus (CPXV), hantavirus (HTV), herpes simplex virus 1 (HSV1) and vesicular stomatitis virus (VSV) and showed antiviral efficacy in human primary respiratory cells. An in vitro resistance development analysis for regorafenib failed to detect IV resistance development against this drug. Taken together, the otherwise clinically approved UBKIs regorafenib and sorafenib possess high and broad-spectrum antiviral activity along with substantial robustness against resistance development and thus constitute attractive host-directed drug candidates against a range of viral infections including influenza.

Conventional medications against influenza infections, including vaccination and antiviral drug therapy, are targeted against viral determinants–an approach collectively referred to as pathogen-directed. However, influenza viruses mutate fast and quickly develop resistance to these pathogen-directed treatments. An alternative, yet not well established, is to block host cellular molecules required by the virus to successfully multiply. Such a host-directed approach is anticipated to be more robust against the development of drug resistance. This notion is founded on the different modes of action of the two principal approaches: Virus-directed therapeutics target the virus itself. Thus, just a single mutation could abrogate sensitivity to a virus-directed therapeutic. In contrast, it is unlikely that viruses can easily circumvent a pharmacological blockage of a cellular factor by means of just a few mutations. Instead, the virus needs to either exploit an immediate parallel cellular pathway or adjust its replication cycle to a different cellular factor–the latter being a process likely to require multiple mutations, if possible at all. To identify the most promising targets for a host-directed therapy, we performed a small interfering RNA (siRNA) screen with four different influenza virus strains using a lung epithelial cell line. Subsequently, we tested a series of drugs, specific for the products of the genes that are required for replication of all four influenza virus strains tested. Regorafenib and sorafenib, two chemically related urea-based kinase inhibitors already clinically approved for cancer treatment, turned out to be effective inhibitors of all influenza viruses and displayed low cytotoxicity. These drugs blocked viral replication at an early stage of the life cycle not only in cell lines but also in human primary respiratory cells. Moreover, these drugs exhibited high efficacy even against unrelated viruses. In addition, no development of resistance was observed against regorafenib, which was used in an in vitro assay representatively of urea-based kinase inhibitors. Our results suggest that regorafenib and sorafenib are promising drug candidates for a host-directed therapy of influenza and other viral infections.

• A549 Cells
• Active Transport, Cell Nucleus/physiology
• Antiviral Agents
• Host-Pathogen Interactions
• Humans
• Influenza A Virus, H5N1 Subtype/genetics
• Influenza A Virus, H5N1 Subtype/immunology
• Influenza A virus/genetics
• Influenza A virus/immunology
• Influenza B virus/genetics
• Influenza B virus/immunology
• Influenza, Human
• Orthomyxoviridae/genetics
• Orthomyxoviridae/immunology
• Orthomyxoviridae/pathogenicity
• Phenylurea Compounds/pharmacology
• Protein Kinase Inhibitors/metabolism
• Pyridines/pharmacology
• RNA Interference/immunology
• RNA Viruses
• RNA, Small Interfering/genetics
• RNA, Small Interfering/immunology
• Sorafenib/pharmacology
• Urea/metabolism
• Virus Replication/physiology

• BMBF
• Deutsche Forschungsgemeinschaft

• Animals
• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Colonic Neoplasms/diagnostic imaging
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Disease Progression
• Dose-Response Relationship, Drug
• Fluorescent Dyes
• Fluorodeoxyglucose F18
• Humans
• Mice, Transgenic
• Molecular Imaging
• Neoplasm Transplantation
• Niacinamide/analogs & derivatives
• Niacinamide/pharmacology
• Optical Imaging
• Phenylurea Compounds/pharmacology
• Positron-Emission Tomography
• Radiopharmaceuticals
• Random Allocation
• Receptors, Bombesin/metabolism
• Receptors, Transferrin/metabolism
• Sorafenib
• Treatment Outcome
• Tumor Burden

• Antiangiogenesis
• Colorectal cancer
• DCE-MRI
• Regorafenib
• Sorafenib
• VEGFR2 signaling

• contrast-enhanced ultrasonography
• hepatocellular carcinoma
• micro-flow imaging
• sorafenib
• therapeutic response

• BZG
• Multikinase inhibitor
• Novel sorafenib analogues
• Pharmacokinetics
• Tissue distribution
• UPLC–MS/MS

Prior tumor cell studies have shown that the drugs sorafenib (Nexavar) and regorafenib (Stivarga) reduce expression of the chaperone GRP78. Sorafenib/regorafenib and the multi‐kinase inhibitor pazopanib (Votrient) interacted with sildenafil (Viagra) to further rapidly reduce GRP78 levels in eukaryotes and as single agents to reduce Dna K levels in prokaryotes. Similar data were obtained in tumor cells in vitro and in drug‐treated mice for: HSP70, mitochondrial HSP70, HSP60, HSP56, HSP40, HSP10, and cyclophilin A. Prolonged ‘rafenib/sildenafil treatment killed tumor cells and also rapidly decreased the expression of: the drug efflux pumps ABCB1 and ABCG2; and NPC1 and NTCP, receptors for Ebola/Hepatitis A and B viruses, respectively. Pre‐treatment with the ‘Rafenib/sildenafil combination reduced expression of the Coxsackie and Adenovirus receptor in parallel with it also reducing the ability of a serotype 5 Adenovirus or Coxsackie virus B4 to infect and to reproduce. Sorafenib/pazopanib and sildenafil was much more potent than sorafenib/pazopanib as single agents at preventing Adenovirus, Mumps, Chikungunya, Dengue, Rabies, West Nile, Yellow Fever, and Enterovirus 71 infection and reproduction. ‘Rafenib drugs/pazopanib as single agents killed laboratory generated antibiotic resistant E. coli which was associated with reduced Dna K and Rec A expression. Marginally toxic doses of ‘Rafenib drugs/pazopanib restored antibiotic sensitivity in pan‐antibiotic resistant bacteria including multiple strains of bla_kpcKlebsiella pneumoniae. Thus, Dna K is an antibiotic target for sorafenib, and inhibition of GRP78/Dna K has therapeutic utility for cancer and for bacterial and viral infections. J. Cell. Physiol. 230: 2552–2578, 2015. © 2015 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.

We determined whether the multi‐kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over‐expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK‐1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re‐expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by ‘rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti‐tumor therapy for solid tumor patients. J. Cell. Physiol. 230: 2281–2298, 2015. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

• Antiproliferative
• CDK inhibitor
• cancer
• molecular modelling
• synthesis

• CYP450
• UDP-glucuronosyltransferases
• glucuronidation
• regorafenib
• sorafenib
• tyrosine kinase inhibitors

Here we report a case of a 76-year-old man with a giant cavernous hepatic hemangioma of more than 20 cm in diameter. Since the hepatic hemangioma was actually growing and might possibly rupture and he complained of abdominal symptoms, we decided to perform interventional therapy. First we performed transcatheter arterial embolization (TAE) of the hepatic arteries. However, since this was not sufficiently effective, we added sorafenib (600 mg/day). As a result, the tumor shrank with symptomatic improvement. Subsequently, an adverse event occurred, and we suspended the sorafenib therapy. Then, the tumor began to grow, and we resumed administering sorafenib at 400 mg/day. The tumor shrank again, and we continued the sorafenib therapy thereafter. The tumor shrinkage, although possibly induced by the effect of TAE, is considered primarily due to the effect of treatment with sorafenib, because (1) TAE did not sufficiently reduce the blood supply to the inside of the tumor; (2) other tumors shrank in the area not targeted by TAE; and (3) the tumor grew during suspension of sorafenib therapy and shrank again after resuming the treatment.

• Hepatic hemangioma
• Sorafenib
• Transcatheter arterial embolization

AIM: To determine the usefulness of arrival time parametric imaging (AtPI) using contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating early response to sorafenib for hepatocellular carcinoma (HCC).

METHODS: Fourteen advanced HCC patients who received sorafenib 400/800 mg/d for at least 4 wk and were followed up by CEUS were enrolled in this study. CEUS was performed before treatment and 2 and 4 wk after treatment, and images of the target lesion in the arterial phase were recorded for each patient. The images were analyzed by AtPI. Color mapping (CM) images obtained by AtPI were compared before and after the treatment. In these CM images, the mean arrival time of the contrast agent in the region of interest from the starting point [mean time (MT)] was calculated. In each patient, differences between MT before and MT 2 and 4 wk after the treatment were compared with responses evaluated 4-8 wk after the treatment by dynamic computed tomography (CT), and statistical analysis was performed. Modified response evaluation criteria in solid tumors was used for the response evaluation.

RESULTS: In CM images both 2 and 4 wk after the treatment, delays in the arrival time of the contrast agent were noted in 8 of the 14 patients. In the other 6 patients, no color changes were observed in the tumor, or red and/or yellow increase, suggesting a decrease in blood flow velocity between images 2 and 4 wk after the treatment and those before the treatment. Dynamic CT could be performed 4-8 wk after the treatment in 13 of the 14 patients. Median differences in the MT were 1.13 s and 1.015 s, 2 and 4 wk after the treatment, respectively, in the 8 patients who showed stable disease (SD)/partial response (PR) on dynamic CT. Median differences in the MT were -0.39 s and -0.95 s, 2 and 4 wk after the treatment, respectively, in the 5 patients who showed progressive disease (PD). Differences in the median MT between SD/PR and PD groups were significant 2 and 4 wk after the treatment with P = 0.019 and P = 0.028, respectively.

CONCLUSION: AtPI by CEUS using Sonazoid is suggested to be useful for evaluating early responses to sorafenib.

• Sorafenib
• Sonazoid
• Contrast-enhanced ultrasonography
• Hepatocellular carcinoma
• Therapeutic response

• Animals
• Antigens, Neoplasm/analysis
• Antigens, Neoplasm/chemistry
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/physiology
• Carcinoma, Hepatocellular/chemistry
• Carcinoma, Hepatocellular/pathology
• Cell Adhesion Molecules/analysis
• Cell Adhesion Molecules/chemistry
• Cell Adhesion Molecules/genetics
• Cell Adhesion Molecules/physiology
• Cell Line, Tumor
• Epithelial Cell Adhesion Molecule
• Humans
• Liver Neoplasms/chemistry
• Liver Neoplasms/pathology
• Mice
• Neoplastic Stem Cells/physiology
• Protein Structure, Tertiary

Large-scale protein signalling networks are useful for exploring complex biochemical pathways but do not reveal how pathways respond to specific stimuli. Such specificity is critical for understanding disease and designing drugs. Here we describe a computational approach—implemented in the free CNO software—for turning signalling networks into logical models and calibrating the models against experimental data. When a literature-derived network of 82 proteins covering the immediate-early responses of human cells to seven cytokines was modelled, we found that training against experimental data dramatically increased predictive power, despite the crudeness of Boolean approximations, while significantly reducing the number of interactions. Thus, many interactions in literature-derived networks do not appear to be functional in the liver cells from which we collected our data. At the same time, CNO identified several new interactions that improved the match of model to data. Although missing from the starting network, these interactions have literature support. Our approach, therefore, represents a means to generate predictive, cell-type-specific models of mammalian signalling from generic protein signalling networks.

• sorafenib
• apoptosis
• cd4⁺
• cd8⁺
• cd3/cd28
• annexin v
• 7aad

• Apoptosis/drug effects
• Apoptosis/physiology
• Benzenesulfonates/pharmacology
• CD28 Antigens/metabolism
• CD3 Complex/metabolism
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/pathology
• Cell Proliferation/drug effects
• Cells, Cultured
• Flow Cytometry
• Humans
• Immunosuppressive Agents/pharmacology
• Interleukin-2/pharmacology
• Interleukin-2 Receptor alpha Subunit/metabolism
• Lymphocyte Activation/drug effects
• Niacinamide/analogs & derivatives
• Phenylurea Compounds
• Protein Kinase Inhibitors/pharmacology
• Pyridines/pharmacology
• Receptors, Antigen, T-Cell/immunology
• Sirolimus/pharmacology
• Sorafenib
• raf Kinases/antagonists & inhibitors
• raf Kinases/metabolism

• R01 CA057653-15 NCI NIH HHS
• P01 CA040042-220011 NCI NIH HHS
• CA77584 NCI NIH HHS
• P30 CA044579 NCI NIH HHS
• P30 CA044579-199019 NCI NIH HHS
• R01 CA077584 NCI NIH HHS
• R01 CA57653 NCI NIH HHS
• R01 CA057653 NCI NIH HHS
• R01 CA077584-09 NCI NIH HHS
• CA40042 NCI NIH HHS
• P30 CA44579 NCI NIH HHS
• P01 CA040042 NCI NIH HHS

• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/surgery
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Mice
• Mice, Nude
• Models, Biological
• Transplantation, Heterologous

• Benzenesulfonates/pharmacology
• Benzenesulfonates/therapeutic use
• Cell Line
• Cell Line, Tumor
• Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
• Humans
• Immunohistochemistry
• Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
• Niacinamide/analogs & derivatives
• Phenylurea Compounds
• Proto-Oncogene Proteins B-raf/antagonists & inhibitors
• Proto-Oncogene Proteins c-raf/antagonists & inhibitors
• Pyridines/pharmacology
• Pyridines/therapeutic use
• Sorafenib

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer (HCC). Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors (“small molecule inhibitors”) and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin (mTOR) upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation. mTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.

• Growth factor receptor
• Hepatocellular cancer
• Small molecule inhibitor
• Monoclonal antibody
• Innovative cancer treatment
• Sorafenib
• Bevacizumab
• Erlotinib

• Aged
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/blood
• Antineoplastic Agents/pharmacokinetics
• Antineoplastic Agents/therapeutic use
• Benzenesulfonates/adverse effects
• Benzenesulfonates/blood
• Benzenesulfonates/pharmacokinetics
• Benzenesulfonates/therapeutic use
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Dose-Response Relationship, Drug
• Female
• Humans
• Japan
• Liver Neoplasms/blood
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Male
• Middle Aged
• Niacinamide/analogs & derivatives
• Phenylurea Compounds
• Pyridines/adverse effects
• Pyridines/blood
• Pyridines/pharmacokinetics
• Pyridines/therapeutic use
• Sorafenib

• Antineoplastic Agents/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Benzenesulfonates/pharmacology
• Cell Cycle/drug effects
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Cell Proliferation/drug effects
• Cholangiocarcinoma/pathology
• Enzyme Activation/drug effects
• Humans
• Mitogen-Activated Protein Kinase 1/metabolism
• Mitogen-Activated Protein Kinase 3/metabolism
• Niacinamide/analogs & derivatives
• Phenylurea Compounds
• Pyridines/pharmacology
• Receptor, IGF Type 1/antagonists & inhibitors
• Sorafenib
• Tumor Cells, Cultured
• Tyrphostins/pharmacology

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Renal Cell/drug therapy
• Carcinoma, Renal Cell/therapy
• Clinical Trials as Topic
• Disease-Free Survival
• Humans
• Interleukin-2/metabolism
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/therapy
• Models, Biological
• Research Design
• Signal Transduction

• Animals
• Humans
• Neoplasms/pathology
• Oncogenes/physiology
• Proto-Oncogene Mas

• R01 CA 098513 NCI NIH HHS

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Enzyme Inhibitors/pharmacology
• Enzyme Inhibitors/therapeutic use
• Humans
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Signal Transduction
• ras Proteins/antagonists & inhibitors
• ras Proteins/chemistry
• ras Proteins/metabolism

• CA-030721 NCI NIH HHS

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Clinical Trials as Topic
• ErbB Receptors/antagonists & inhibitors
• Humans
• Lung Neoplasms/drug therapy
• Protein Kinase Inhibitors/administration & dosage

• CA49957 NCI NIH HHS
• CA68485 NCI NIH HHS
• P50 CA90949 NCI NIH HHS