RESUMEN

Controllable gene expression is a desirable feature both in gene therapy protocols and for the study of gene function in animals and plants. We have exploited the modular character of the tetracycline (tc)-regulatable genetic switch to show that its components can be encoded by any combination of recombinant adenovirus and/or transgenic mice. Transgenic mice were constructed that express the tc-regulatable trans-activator tTA muscle specifically. These were injected with recombinant adenovirus expressing a luciferase reporter controlled by the tTA-regulatable promoter. Virus injected into muscle, but not into a control organ (brain) resulted in luciferase activity. Conversely, injection of tTA producing adenovirus into mice that were transgenic for a trkB/Fc fusion protein gene under tc promoter control resulted in swift expression of serum trkB/Fc receptor-body. Both modes of gene induction were fully inhibited by administration of tc. We demonstrate that a careful choice of these tools allows exquisite in vivo control over transgene expression in a temporal, tc-regulatable, topical and tissue-specific manner.

Asunto(s)

Regulación de la Expresión Génica , Terapia Genética/métodos , Regiones Promotoras Genéticas , Inhibidores de la Síntesis de la Proteína/farmacología , Tetraciclina/farmacología , Transactivadores/efectos de los fármacos , Adenoviridae , Animales , Northern Blotting , Cruzamiento , Vectores Genéticos , Luciferasas/genética , Ratones , Ratones Transgénicos , Músculo Esquelético/enzimología , Activación Transcripcional , Transfección/métodos

RESUMEN

The E-selectin cell adhesion protein plays a critical role in mediating adherence of leukocytes to endothelium at sites of inflammation. Cytokine-induced E-selectin expression on the surface of endothelial cells is transient; mRNA expression peaks at 3-4 h after induction and returns to basal levels within 24 h. The mechanism for this transcriptional down-modulation is not known. Promoter binding factors responsible for induced gene expression include NF-kappaB, which binds at three sites within the E-selectin promoter, and HMG-I(Y), which binds to the A/T-rich core found at the centre of these binding sites. Distamycin is an antibiotic that also binds A/T-rich DNA and inhibits HMG-I(Y) DNA binding. To study the role of HMG-I(Y) in E-selectin expression, we have examined the effect of distamycin on the cytokine-induced E-selectin expression cycle. We found that distamycin prolonged E-selectin expression, both by sustaining mRNA transcription and by extending the transcript's half-life. The distamycin effect on transcription was mediated through one of the three NF-kappaB-HMG-I(Y) binding sites (NF-kappaBII) within the promoter. This suggests that the NF-kappaB-HMG-I(Y) complex interacting at the NF-kappaBII site plays a role not only in cytokine induction of E-selectin expression, but also in its down-modulation.

Asunto(s)

Distamicinas/farmacología , Selectina E/metabolismo , Regulación de la Expresión Génica/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , FN-kappa B/metabolismo , Regiones Promotoras Genéticas/genética , Sitios de Unión/genética , Northern Blotting , Células Cultivadas , Huella de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo/fisiología , Selectina E/genética , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Citometría de Flujo , Genes Reporteros/genética , Proteína HMGA1a , Humanos , Interleucina-1/farmacología , Conformación de Ácido Nucleico , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/farmacología

RESUMEN

Commercially available and widely used cat expression vectors were found to contain a forskolin (Fs)-inducible element capable of co-operation with NF-kappa B-sites in test promoters. An alternative NF-kappa B-dependent reporter system is presented that allows investigation of the effects of Fs and other agents that augment intracellular cyclic AMP.

Asunto(s)

Moléculas de Adhesión Celular/genética , Cloranfenicol O-Acetiltransferasa/biosíntesis , AMP Cíclico/metabolismo , Endotelio/metabolismo , Elementos de Facilitación Genéticos , Vectores Genéticos , FN-kappa B/metabolismo , Regiones Promotoras Genéticas , Transcripción Genética , Sitios de Unión , Moléculas de Adhesión Celular/biosíntesis , Células Cultivadas , Cloranfenicol O-Acetiltransferasa/genética , Colforsina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Selectina E , Inducción Enzimática , Humanos , Venas Umbilicales

RESUMEN

Cytokines induce the expression of E-selectin, VCAM-1, and ICAM-1 on human umbilical vein endothelial cells (HUVECs). We show that expression of these surface proteins is differently affected by cAMP. Increased cAMP levels decrease E-selectin and VCAM-1 but increase ICAM-1 expression. We demonstrate by mRNA half-life analysis and nuclear run-on assays that the cAMP repression of E-selectin occurs at the transcription level. This effect is abolished by protein kinase A inhibition, suggesting that repression is mediated by protein kinase A-driven phosphorylation. We found that a minimal E-selectin promoter sequence necessary to confer cytokine inducibility is also sufficient to mimic the cAMP effect in transfected HUVECs. Previously we characterized two regions (NF-kappa B and NF-ELAM1) of the minimal promoter that bind transcription factors necessary for E-selectin induction, Increased cAMP did not alter the binding of the complexes formed on either the NF-kappa B or NF-ELAM1 site. In contrast, in interleukin-1-treated HUVECs transactivity due to an NF-kappa B site is reduced by elevated cAMP. Increased cAMP in HUVECs appears to induce a protein kinase activity that reduces the cytokine signal for E-selectin and VCAM-1 expression. The reduction in signal may occur through an inhibitory phosphorylation of one or more of the factors responsible for regulating E-selectin expression.

Asunto(s)

Moléculas de Adhesión Celular/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Transcripción Genética , Secuencia de Bases , Adhesión Celular , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Colforsina/farmacología , AMP Cíclico/metabolismo , ADN/metabolismo , Selectina E , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Datos de Secuencia Molecular , Proteínas Nucleares/metabolismo , Oligodesoxirribonucleótidos , Fosforilación , Regiones Promotoras Genéticas , Acetato de Tetradecanoilforbol/farmacología , Molécula 1 de Adhesión Celular Vascular

RESUMEN

We previously reported that NF-kappa B and a complex we referred to as NF-ELAM1 play a central role in cytokine-induced expression of the E-selectin gene. In this study we identify cyclic AMP (cAMP)-independent members of the ATF family binding specifically to the NF-ELAM1 promoter element. The NF-ELAM1 element (TGACATCA) differs by a single nucleotide substitution from the cAMP-responsive element consensus sequence. We demonstrate that this sequence operates in a cAMP-independent manner to induce transcription and thus define it as a non-cAMP-responsive element (NCRE). We show that ATFa is a component of the NF-ELAM1 complex and its overexpression activates the E-selectin promoter. In addition, ATFa, ATF2, and ATF3 interact directly with NF-kappa B in vitro, linking two unrelated families of transcription factors in a novel protein-protein interaction. Furthermore, we demonstrate that the ability of overexpressed NF-kappa B to transactivate the E-selectin promoter in vivo is dependent on the NF-ELAM1 complex. Our results suggest that a direct interaction between ATFs and NF-kappa B is, at least in part, the mechanism by which these factors specifically regulate E-selectin promoter activity.

Asunto(s)

Proteínas Sanguíneas/metabolismo , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , AMP Cíclico/farmacología , Citocinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , FN-kappa B/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismo , Factores de Transcripción Activadores , Secuencia de Bases , Sitios de Unión , Clonación Molecular , Colforsina/farmacología , ADN Complementario/biosíntesis , ADN Complementario/metabolismo , Selectina E , Endotelio Vascular/metabolismo , Biblioteca de Genes , Glutatión Transferasa/biosíntesis , Glutatión Transferasa/metabolismo , Células HeLa , Humanos , Leucina Zippers , Glicoproteínas de Membrana/biosíntesis , Datos de Secuencia Molecular , Proteínas de Neoplasias/metabolismo , Sondas de Oligonucleótidos , Plásmidos , Regiones Promotoras Genéticas/efectos de los fármacos , Proteínas Recombinantes de Fusión/metabolismo , Venas Umbilicales

RESUMEN

E-selectin is an adhesion molecule transiently and specifically expressed on endothelial cells upon stimulation with cytokines. We wished to determine whether methylation could play a role in cell-type specific expression of this gene. We found that the E-selectin promoter in cultured endothelial cells is under-methylated in comparison with non-expressing HeLa cells. Plasmid constructs carrying a reporter driven by the E-selectin promoter and methylated in vitro are no longer transcribed in either an in vitro transcription system or in transiently transfected cells. We identified the NF-kappa B site in the promoter as the likely target for this methylation-mediated repression by testing a minimal promoter carrying only this and an associated element. We conclude that methylation is likely to play a role in blocking E-selectin expression in non-endothelial cells.

Asunto(s)

Moléculas de Adhesión Celular/genética , ADN/metabolismo , Endotelio Vascular/metabolismo , Glicoproteínas de Membrana/genética , FN-kappa B/antagonistas & inhibidores , Regiones Promotoras Genéticas , Secuencia de Bases , Células Cultivadas , Cromatografía de Afinidad , ADN/aislamiento & purificación , Selectina E , Células HeLa , Humanos , Metilación , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Plásmidos , Reacción en Cadena de la Polimerasa , Transcripción Genética , Activación Transcripcional , Transfección , Venas Umbilicales

RESUMEN

Endothelial leukocyte adhesion molecule-1 (ELAM-1) is a membrane protein exclusively expressed on endothelial cells, where it plays a key role in the inflammatory response by adhering to a subset of leukocytes. The expression of the ELAM-1 gene is very tightly regulated. ELAM-1 is undetectable in uninduced cells, and it is transiently expressed following cytokine induction. Treatment of resting endothelial cells with three different protein synthesis inhibitors, cycloheximide (CHX), anisomycin, and emetine, caused an increase in the steady-state level of ELAM-1 mRNA above that observed with IL (interleukin)-1 alone. Furthermore, ELAM-1 mRNA was found in the presence of all three protein synthesis inhibitors without IL-1 treatment. Analysis of the mRNA half-life indicated that the protein synthesis inhibitors act, in part, by stabilizing ELAM-1 mRNA. In addition, protein synthesis inhibitors potentiate the effect of IL-1 beta at the level of transcription initiation as shown by nuclear run-on experiments. The NF kappa B-like binding activity to the ELAM-1 promoter sequence induced by IL-1 beta is augmented by inhibitors of protein synthesis. The NF kappa B binding sequence was found to be necessary and sufficient for superinduction of the ELAM-1 gene by CHX. These results show that regulation at the level of protein synthesis is implicated in the overall regulation of ELAM-1 gene expression. Mechanisms which could explain these effects are discussed.

Asunto(s)

Moléculas de Adhesión Celular/genética , Endotelio Vascular/fisiología , Secuencia de Bases , Células Cultivadas , Selectina E , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Técnicas In Vitro , Interleucina-1/farmacología , Datos de Secuencia Molecular , FN-kappa B/metabolismo , Regiones Promotoras Genéticas , Inhibidores de la Síntesis de la Proteína/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción Genética/efectos de los fármacos

RESUMEN

The endothelial leukocyte adhesion molecule 1 (ELAM-1) is transiently expressed specifically on the surface of cytokine-induced endothelial cells. We demonstrate that the transient expression of the protein is paralleled by an increase and decrease in transcription of the ELAM-1 gene. To identify the cis-acting transcription control regions within the ELAM-1 gene that are responsible for this cytokine-induced expression, we isolated and analyzed an ELAM-1 genomic clone containing sequences upstream of the transcription start site. We constructed a series of ELAM-1 deletion mutants linked to a reporter gene and analyzed their expression in both endothelial and non-endothelial cells. Results show that a fragment of 233 bp upstream of the transcription start site is sufficient to confer cytokine inducibility upon the reporter gene in both endothelial and non-endothelial cells. Further analysis defined two elements within this region that are involved in the cytokine inducibility of the ELAM-1 gene. One element lies within the -233 to -117 region, the other element represents an NF kappa B consensus binding site between nucleotides -94 to -85. Gel shift analysis reveals increased binding of an NF kappa B-like factor to this consensus sequence in extracts prepared from IL-1-induced endothelial cells. The results suggest that cytokine induction of ELAM-1 gene transcription is imparted by a combination of positive factors, one being an NF kappa B-like transcription factor, interacting with cis-acting elements within the enhancer/promoter of the gene.

Asunto(s)

Moléculas de Adhesión Celular/genética , Regulación de la Expresión Génica/fisiología , FN-kappa B/fisiología , Transcripción Genética/fisiología , Secuencia de Bases , Adhesión Celular/genética , Moléculas de Adhesión Celular/biosíntesis , Células Cultivadas , Clonación Molecular , Secuencia de Consenso , ADN , Selectina E , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Elementos de Facilitación Genéticos , Humanos , Interleucina-1/fisiología , Datos de Secuencia Molecular , Mutagénesis , Regiones Promotoras Genéticas

RESUMEN

The gene coding for the key glycolytic enzyme fructose-1,6-diphosphate aldolase of the human malaria parasite Plasmodium falciparum lacks a functional AUG initiation codon for translation. Protein sequences of natural or in vitro translated aldolase include the candidate start methionine residue at internal positions. No additional AUG start codon is found in genomic DNA, cDNA or mRNA sequences. Instead, a UAG chain termination codon is recognized as the start signal of protein synthesis in vivo and in vitro.

Asunto(s)

Fructosa-Bifosfato Aldolasa/genética , Plasmodium falciparum/genética , Biosíntesis de Proteínas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Codón/genética , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Plasmodium falciparum/enzimología , ARN Mensajero/genética , Reticulocitos/metabolismo , Regiones Terminadoras Genéticas/genética

RESUMEN

Asexual blood stage proliferation is responsible for the morbidity and mortality associated with malaria infection in man. These developmental stages are therefore obvious targets for the development of malaria vaccines. Several asexual blood stage components have been identified as potential candidates for the development of vaccines and some of them have been shown, following immunization, to induce at least partial protection in a variety of Plasmodium-host combinations. Studies on defined parasite components and on synthetic peptides derived from them have revealed new insights at the molecular level into parasite mechanisms involved in propagation and survival in the infected host, and into the interaction between parasite components and the host immune system. Practical application of these findings is likely to provide the basis for the design of more appropriate antigens for the development of vaccines.

Asunto(s)

Malaria/prevención & control , Plasmodium/inmunología , Vacunas , Animales , Antígenos de Protozoos/inmunología , Antígenos de Superficie/inmunología , Humanos , Péptidos/inmunología , Proteínas Protozoarias/inmunología , Vacunas Sintéticas

RESUMEN

The plasmid ColD-CA23, a high copy number plasmid of 5.12 kb, contains genes for colicin D (cda), for immunity colicin D (cdi), and for a lysis function (cdl). These genes are arranged on a contiguous 2.4 kb fragment in the following sequence: cda, cdi, cdl. They are transcribed in two operons, one transcribing cda and cdl from a SOS inducible promoter, the other transcribing cdi in the opposite direction. The expression of cda and cdl is modulated by a repressor, cdr, which is encoded on the same transcript as cda and cdl. In the absence of this repressor, transcription from the SOS inducible colicin D promoter is exceptionally strong and leads to protein contents up to 50% of total cellular proteins. This autoregulative repressor is a new finding in the control mechanisms of expression of colicins. We have also identified the gene product of cdl to be a 10,000 dalton protein.

Asunto(s)

Colicinas/genética , Escherichia coli/genética , Regulación de la Expresión Génica , Genes Bacterianos , Plásmidos , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Sitios de Unión , Enzimas de Restricción del ADN , ARN Polimerasas Dirigidas por ADN/metabolismo , Genes , Operón , Unión Proteica , Transcripción Genética

RESUMEN

Immunization with a 41-kilodalton blood stage antigen (p41) of Plasmodium falciparum induces immunity to malaria in monkeys. However, antigenic polymorphism and repetitive amino acids commonly found in protective antigens complicate vaccine development. The gene encoding p41 has now been cloned and analyzed. Sequencing and hybridization studies revealed that the gene structure is highly conserved in 14 parasite isolates from three continents. This finding and the lack of repetitive amino acids in the translated DNA sequence may indicate that p41 has an essential function. In this study the protein was found to be 60 percent homologous to the key glycolytic enzyme aldolase from vertebrates, and the affinity-purified p41 protein from parasites showed aldolase activity.

Asunto(s)

Antígenos de Protozoos/inmunología , Fructosa-Bifosfato Aldolasa/metabolismo , Plasmodium falciparum/inmunología , Animales , Anticuerpos Antiprotozoarios/inmunología , Complejo Antígeno-Anticuerpo/análisis , Antígenos de Protozoos/genética , Fructosa-Bifosfato Aldolasa/genética , Fructosa-Bifosfato Aldolasa/inmunología , Cinética , Plasmodium falciparum/enzimología , Polimorfismo Genético

RESUMEN

Cell-free translation of total RNA from rabbit intestinal mucosa in a rabbit reticulocyte lysate, after immunoprecipitation with antibodies directed against sucrase-isomaltase, yielded a polypeptide of 200 kDa, which was identified as pro-sucrase-isomaltase. Addition of dog pancreatic microsomal vesicles to the translation system resulted in the appearance of an additional 220-kDa polypeptide. The 220-kDa polypeptide was associated with the membranes in a way that made it inaccessible to proteolysis; this protection was abolished by lytic detergent concentrations, indicating that the polypeptide was segregated into the microsomal vesicle. The 220-kDa polypeptide was glycosylated as evidenced by it being bound to concanavalin A-Sepharose and eluted with alpha-methyl-D-mannopyranoside. The increase in apparent molecular mass (approximately 20 kDa) of the primary translation product upon translocation was due to the addition of carbohydrate; treatment of the 220-kDa polypeptide with endo-beta-N-acetylglucosaminidase H increased its electrophoretic mobility to that of the 200-kDa polypeptide which was obtained in the absence of membranes. Partial N-terminal amino acid sequence of a translation product labeled with [3H]Leu in the absence of membranes revealed that Leu was incorporated into identical positions as in the final (pro)-sucrase-isomaltase, thus indicating the lack of a transient signal peptide.

Asunto(s)

Precursores Enzimáticos/genética , Mucosa Intestinal/enzimología , Complejos Multienzimáticos/genética , Biosíntesis de Proteínas , Complejo Sacarasa-Isomaltasa/genética , Animales , Membrana Celular/enzimología , Sistema Libre de Células , Perros , Precursores Enzimáticos/biosíntesis , Precursores Enzimáticos/aislamiento & purificación , Glicoproteínas/biosíntesis , Glicoproteínas/genética , Glicoproteínas/aislamiento & purificación , Membranas Intracelulares/metabolismo , Microsomas/metabolismo , Peso Molecular , Páncreas/metabolismo , Procesamiento Proteico-Postraduccional , Conejos , Reticulocitos/metabolismo , Complejo Sacarasa-Isomaltasa/biosíntesis , Complejo Sacarasa-Isomaltasa/aislamiento & purificación

RESUMEN

The plasmid ColD-CA23, a high-copy-number plasmid of 5.12 kilobases, encodes colicin D, a protein of approximately 87,000 daltons which inhibits bacterial protein synthesis. Colicin D production is under the control of the Escherichia coli SOS regulatory system and is released to the growth medium via the action of the lysis gene product(s). A detailed map of the ColD plasmid was established for 10 restriction enzymes. Using in vitro insertional omega mutagenesis and in vivo insertional Tn5 mutagenesis, we localized the regions of the plasmid responsible for colicin D activity (cda), for mitomycin C-induced lysis (cdl), and for colicin D immunity (cdi). These genes were all located contiguously on a 2,400-base-pair fragment similar to a large number of other Col plasmids (A, E1, E2, E3, E8, N, and CloDF). The ColD plasmid was mobilizable by conjugative transfer by helper plasmids of the IncFII incompatibility group, but not by plasmids belonging to the groups IncI-alpha or IncP. The location of the mobilization functions was determined by deletion analysis. The plasmid needs a segment of 400 base pairs, which is located between the mob genes and the gene for autolysis, for its replication.

Asunto(s)

Colicinas/genética , Genes Bacterianos , Plásmidos , Colicinas/biosíntesis , Colicinas/inmunología , Conjugación Genética , Replicación del ADN , Elementos Transponibles de ADN , ADN Bacteriano/análisis , Mutación

RESUMEN

The apparent subcellular distribution of adriamycin (ADM) was investigated in the liver and primary or metastatic tumor tissue of C57BL/6 mice bearing i.m. 3LL. ADM was measured by a fluorimetric assay in the various cell components, nuclei (N), mitochondria (MT), microsomes (M) and soluble fraction of cytoplasm (SF), either in vitro at various times of incubation or in vivo after drug injection. In both experimental conditions more than 50% of ADM accumulated in nuclei, whereas only a proportionally low amount of drug has recovered in the other fractions. However, a progressive increase in the percentage of drug stored in M and particularly in MT was noted in vivo in both liver and tumor, reaching in MT 3 times the starting amount on a percentage basis 24 hr after drug treatment. The elimination half-life of ADM was consistently longer in MT and M than in nuclei and total liver, suggesting that M and particularly MT have a higher capacity than nuclei to retain the drug. Work is in progress to evaluate whether this higher ADM accumulation at these subcellular sites is related to higher specific affinity or more persistent binding, like covalent binding to macromolecules, possibly accounting for the mitochondrial injury usually observed after treatment with ADM.

Asunto(s)

Doxorrubicina/metabolismo , Hígado/metabolismo , Neoplasias Pulmonares/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Mitocondrias Hepáticas/metabolismo , Neoplasias Experimentales/metabolismo , Fracciones Subcelulares/metabolismo , Factores de Tiempo

Asunto(s)

Membrana Celular/enzimología , Precursores Enzimáticos/genética , Intestino Delgado/enzimología , Microvellosidades/enzimología , Complejos Multienzimáticos/genética , Biosíntesis de Proteínas , Complejo Sacarasa-Isomaltasa/genética , Animales , Sistema Libre de Células , Mucosa Intestinal/enzimología , Peso Molecular , ARN Mensajero/genética , Conejos , Reticulocitos/metabolismo

RESUMEN

About 30-70% of microsomal hydroxylation of aniline, 0-demethylation of 4-NO2-anisole, N-demethylation of aminopyrine, were lost when whole organs were frozen and kept at low temperatures (0 degrees, -20 degrees, -196 degrees C). When 9000 X g or 105000 X g fractions were prepared from fresh liver and subsequently frozen to different temperatures, there was little or no such loss of activity. The kinetics of the decrease in microsomal enzyme activities was followed during storage of frozen or freeze-dried microsomes at various temperatures. N-demethylation of aminopyrine appeared to be the most sensitive marker of microsome denaturation.

Asunto(s)

Microsomas Hepáticos/enzimología , Conservación de Tejido/métodos , Aminopirina/metabolismo , Compuestos de Anilina/metabolismo , Animales , Calcio/farmacología , Frío , Citocromos/metabolismo , Liofilización , Hidroxilación , Masculino , Ratas , Factores de Tiempo

Asunto(s)

Mecloretamina/farmacología , Warfarina/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Aberraciones Cromosómicas , Cromosomas Humanos/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Mitosis/efectos de los fármacos

RESUMEN

The distribution of adriamycin (AM) in C57Bl/6 mice bearing intramuscular Lewis lung carcinoma under the influence of combined treatment with warfarin (W) was investigated by a fluorimetric procedure. AM was injected IV at the dose of 7.5 mg/kg 14 days after tumor transplantation and W was given in the drinking water for 96 h, starting 24 h before AM.. No substantial modifications in the serum and tissue distribution of AM fluorescence were observed under combined short-term treatment with W.

Asunto(s)

Carcinoma/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Warfarina/administración & dosificación , Animales , Carcinoma/metabolismo , Doxorrubicina/metabolismo , Quimioterapia Combinada , Cinética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Warfarina/metabolismo