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1.
Cancer Chemother Pharmacol ; 62(4): 605-20, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18030469

ABSTRACT

PURPOSE: Erlotinib, a small molecule inhibitor of the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR), increases survival of advanced non-small cell lung cancer patients who failed standard chemotherapy (Phase III study). We evaluated whether erlotinib is also effective at an early stage of primary lung tumorigenesis in a carcinogen-induced lung tumor model in mice. METHODS: Sixteen weeks after carcinogen (urethane) injection, when small self-contained adenomas are evident, male and female A/J mice were treated IP with 10 mg/kg erlotinib or Captisol vehicle daily over 3.5 weeks (15 mice per group). The efficacy, metabolism and mechanism of action of erlotinib were evaluated. RESULTS: Erlotinib reduced tumor burden in males by twofold compared to vehicle (12.7 +/- 1.2 vs 26.2 +/- 2.5 mg, respectively; p < 0.0001), while tumor burden in erlotinib-treated females slightly increased compared to vehicle by 21% (15.1 +/- 1.2 vs 11.9 +/- 0.9 mg, respectively; p < 0.05). Tumor multiplicity, in contrast, was unaffected by erlotinib. The levels of erlotinib that accumulated in plasma, lung tumor tissue and adjacent uninvolved (UI) lung were comparable in males and females. Males, however, accumulated more OSI-420, an active and pharmacologically equipotent metabolite of erlotinib, than females in plasma, lung tumors, and UI lung. In both genders, 80% of tumors contained Kras mutations at codon 61, but no EGFR mutations were detected. The cellular distribution and concentration of EGFR were also similar between genders. In control mice, however, phosphorylated EGFR (pEGFR) levels were nearly 2.5-fold higher in males compared to females in UI lungs and sevenfold higher in lung tumors. Further, erlotinib decreased the contents of pEGFR in UI lungs and lung tumors, particularly in males. CONCLUSIONS: Adenomas from male mice in this early lung cancer model are responsive to erlotinib treatment, possibly because of a greater dependence of male tumor growth on the EGFR pathway compared to females. Importantly, these results indicate that small lung adenomas from male mice that utilize EGFR signaling but also harbor Kras mutations shrink in response to erlotinib, suggesting that erlotinib may be beneficial for some patients very early during lung cancer progression.


Subject(s)
Adenoma/drug therapy , Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Adenoma/genetics , Adenoma/metabolism , Animals , Antineoplastic Agents/metabolism , Body Weight/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Erlotinib Hydrochloride , Female , Injections, Intraperitoneal , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Male , Mice , Mice, Inbred Strains , Mutation , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Quinazolines/metabolism , Sex Factors
2.
Cancer Lett ; 241(2): 197-202, 2006 Sep 28.
Article in English | MEDLINE | ID: mdl-16337739

ABSTRACT

Inbred mice vary in their susceptibility to develop macroscopic, chemically-induced, pulmonary neoplasias. It is not known, however, whether microscopic lesions appear in resistant strains but do not grow or if no early lesions arise at all. We show herein that resistant C57BL/6J (B6) and intermediately resistant BALB/cByJ (BALB) mice form very few urethane-induced early microadenomas (i.e. adenomas larger than hyperplasic foci, but detectable only by light microscopy). Additionally, while all urethane-induced microadenomas in sensitive A/J mice gave rise to adenomas, most microscopic tumors induced in BALB mice by 2-stage, 3-methylcholanthrene/butylated hydroxytoluene carcinogenesis spontaneously regressed. The formation of microscopic lesions is thus genetically dependent, but whether they continue to grow or regress depends on how they were induced.


Subject(s)
Adenoma/chemically induced , Butylated Hydroxytoluene/toxicity , Lung Neoplasms/chemically induced , Methylcholanthrene/toxicity , Mutagens/toxicity , Urethane/toxicity , Adenoma/genetics , Adenoma/pathology , Animals , Cell Transformation, Neoplastic/drug effects , Disease Susceptibility , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred A , Mice, Inbred BALB C , Mice, Inbred C57BL
3.
Am J Pathol ; 167(6): 1763-75, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16314486

ABSTRACT

Human adenocarcinoma (AC) is the most frequently diagnosed human lung cancer, and its absolute incidence is increasing dramatically. Compared to human lung AC, the A/J mouse-urethane model exhibits similar histological appearance and molecular changes. We examined the gene expression profiles of human and murine lung tissues (normal or AC) and compared the two species' datasets after aligning approximately 7500 orthologous genes. A list of 409 gene classifiers (P value <0.0001), common to both species (joint classifiers), showed significant, positive correlation in expression levels between the two species. A number of previously reported expression changes were recapitulated in both species, such as changes in glycolytic enzymes and cell-cycle proteins. Unexpectedly, joint classifiers in angiogenesis were uniformly down-regulated in tumor tissues. The eicosanoid pathway enzymes prostacyclin synthase (PGIS) and inducible prostaglandin E(2) synthase (PGES) were joint classifiers that showed opposite effects in lung AC (PGIS down-regulated; PGES up-regulated). Finally, tissue microarrays identified the same protein expression pattern for PGIS and PGES in 108 different non-small cell lung cancer biopsies, and the detection of PGIS had statistically significant prognostic value in patient survival. Thus, the A/J mouse-urethane model reflects significant molecular details of human lung AC, and comparison of changes in orthologous gene expression may provide novel insights into lung carcinogenesis.


Subject(s)
Adenocarcinoma/genetics , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , Animals , Carcinogens , Cluster Analysis , DNA Replication/genetics , Databases, Nucleic Acid , Disease Models, Animal , Enzymes/genetics , Gene Expression Profiling , Humans , Lung/pathology , Male , Mice , Mice, Inbred A , Neovascularization, Pathologic/genetics , Oligonucleotide Array Sequence Analysis , Species Specificity
4.
Mol Carcinog ; 41(4): 187-96, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15390079

ABSTRACT

Pre-mRNA processing is an important mechanism for globally modifying cellular protein composition during tumorigenesis. To understand this process during lung cancer, expression of two key pre-mRNA alternative splicing factors was compared in a mouse model of early lung carcinogenesis and during regenerative growth following reversible lung injury. Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and alternative splicing factor/splicing factor 2 (ASF/SF2) act antagonistically to modulate splice site selection. Both hnRNP A1 and ASF/SF2 contents rose in adenomas and during injury-induced hyperplasia compared to control lungs, as measured by immunoblotting. While both proteins increased similarly during compensatory hyperplasia, hnRNP A1 increased to a much greater extent than ASF/SF2 in tumors, resulting in a 6-fold increase of the hnRNP A1 to ASF/SF2 ratio. Immunohistochemical analysis showed that hnRNP A1 localized exclusively within tumor nuclei, while ASF/SF2 appeared in cytoplasm and/or nuclei, depending on the growth pattern of the tumor cells. We also demonstrated cancer-associated changes in the pre-mRNA alternative splicing of CD44, a membrane glycoprotein involved in cell-cell and cell-extracellular matrix interactions. hnRNP A1 and ASF/SF2 expression is thus differentially altered in neoplastic lung cells by mechanisms that do not strictly arise from increased cell division. These changes are influenced by tumor histology and may be associated with production of variant CD44 mRNA isoforms.


Subject(s)
Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , RNA Precursors/metabolism , RNA Splicing , RNA-Binding Proteins/metabolism , Alternative Splicing/genetics , Animals , Butylated Hydroxytoluene/pharmacology , Cell Proliferation , Cell Transformation, Neoplastic/chemically induced , Heterogeneous Nuclear Ribonucleoprotein A1 , Hyaluronan Receptors/genetics , Hyperplasia/chemically induced , Hyperplasia/metabolism , Lung Neoplasms/chemically induced , Male , Mice , Mice, Inbred BALB C , Neoplasm Staging , Protein Isoforms/genetics , Protein Transport , RNA Precursors/genetics , RNA Splicing/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Serine-Arginine Splicing Factors
5.
Biochemistry ; 41(15): 4891-900, 2002 Apr 16.
Article in English | MEDLINE | ID: mdl-11939784

ABSTRACT

The p58 subunit of human DNA primase contains a region, M288-K344, that is homologous to part of the 8 kDa domain of DNA polymerase beta. Since regions of a protein that are highly conserved evolutionarily often play important catalytic functions, we examined the effects of mutating this region of the p58 subunit on primase activity. Deleting M288-L313 of the p58 subunit results in a protein that binds to the primase p49 subunit but cannot support primer synthesis on any template when assays only contain Mg(2+) as the divalent metal. Including Mn(2+), a metal that stimulates initiation of primer synthesis, in the assays now allows the enzyme to synthesize primers at a rate only moderately lower than that of the wild-type enzyme on templates consisting solely of deoxycytidylates. While the enzyme is active under these conditions, it has lost the ability to synthesize primers of defined length (i.e., count). Alanine scanning mutagenesis of charged residues in this region revealed three amino acids, R302, R306, and K314, that play important roles in both primer initiation and translocation. Conversion of these residues to alanine interfered with initiation and significantly decreased the processivity of primase. Together, these studies indicate that this "pol beta-like" region of p58 is important for three distinct aspects of primer synthesis:; initiation, translocation, and counting. The implications of these results with respect to the biological role of the p58 subunit and the mechanism of primer synthesis are discussed.


Subject(s)
DNA Primase/chemistry , DNA Primase/metabolism , Amino Acid Sequence , Base Sequence , Conserved Sequence , DNA Polymerase beta/chemistry , Humans , Kinetics , Molecular Sequence Data , Protein Subunits , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Deletion , Sequence Homology, Amino Acid , Templates, Genetic
6.
Hum Gene Ther ; 13(4): 543-51, 2002 Mar 01.
Article in English | MEDLINE | ID: mdl-11874632

ABSTRACT

Ganciclovir (GCV) is widely used as a prodrug for selective activation in tumor cells expressing herpes simplex virus thymidine kinase (HSV-TK) because of its ability to induce multi-log cytotoxicity to HSV-TK-expressing as well as nonexpressing bystander cells. We now report that another substrate for HSV-TK, D-carbocyclic 2'-deoxyguanosine (CdG), induces multi-log cytotoxicity in HSV-TK-expressing and bystander cells at concentrations

Subject(s)
Antiviral Agents/pharmacology , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/pharmacology , Ganciclovir/pharmacology , Prodrugs/pharmacology , Thymidine Kinase/biosynthesis , Viral Proteins/biosynthesis , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Cell Death/drug effects , Cell Death/genetics , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Colonic Neoplasms/virology , Deoxyguanosine/metabolism , Deoxyguanosine/therapeutic use , Enzyme Activation/drug effects , Ganciclovir/metabolism , Ganciclovir/therapeutic use , Gene Transfer Techniques , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/virology , Prodrugs/metabolism , Prodrugs/therapeutic use , Simplexvirus/enzymology , Thymidine Kinase/genetics , Tumor Cells, Cultured
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