RESUMEN
We studied the effect of a new targeted drug Pefagtal that represents a conjugate in which the MS2 phage filled with a substance toxic to cells (thallium salts) is covalently linked to peptides containing the RGD motif. The antitumor and pronounced antimetastatic effects of Pefagtal were demonstrated on transplanted mouse tumors differing in histological type and status of metastasis: Krebs-2 ascites adenocarcinoma of the mammary gland, Lewis lung adenocarcinoma, hepatoma-29, and lung adenocarcinoma. It is assumed that the RGD motif mediates primary binding of the construct to αvß3 and αvß5 integrins that are predominantly overexpressed in the endothelial cells of tumor blood vessels and in tumor and metastatic cells.
Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Células Endoteliales/metabolismo , Integrina alfaVbeta3/metabolismo , Ratones , Oligopéptidos/química , Oligopéptidos/farmacologíaRESUMEN
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a repair enzyme for 3'-end DNA lesions, predominantly stalled DNA-topoisomerase 1 (Top1) cleavage complexes. Tdp1 is a promising target for anticancer therapy based on DNA damage caused by Top1 poisoning. Earlier, we have reported about usnic acid enamine derivatives that are Tdp1 inhibitors sensitizing tumor cells to the action of Top1 poison (Zakharenko in J Nat Prod 79:2961-2967, 2016). In the present work, we showed a sensitizing effect of an enamine derivative of usnic acid (when administered intragastrically) on Lewis lung carcinoma in mice in combination with topotecan (TPT, Top1 poison used in the clinic). In the presence of the usnic acid derivative, both the volume of the primary tumor and the number of metastases significantly diminished. The absence of acute toxicity of this compound was demonstrated, as was the importance of the method of its administration for the manifestation of the sensitizing properties.
Asunto(s)
Benzofuranos/farmacología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/fisiología , Topotecan/uso terapéutico , Animales , Carcinoma Pulmonar de Lewis/patología , Femenino , Masculino , Ratones , Ratones Endogámicos , Metástasis de la Neoplasia , Trasplante de NeoplasiasRESUMEN
The antimetastatic activity of combined or individual administration of topotecan and tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitor was examined under various administration schedules in mice with Lewis lung carcinoma modeled by intravenous injection of 200,000 clone/mouse. The greatest antimetastatic effect was observed after combined use of topotecan and Tdp1 inhibitor as documented by macroscopic study of the lungs that revealed the decreased metastatic scores by 76, 91, or 74% at the respective inhibitor doses of 2, 4, or 6 mg/mouse, respectively, in parallel with inhibition of metastasis up to 98% (at inhibitor dose of 4 mg/mouse) and morphological and morphometric analyses of the lung sections, which revealed elevation of metastasis growth delay index to 86 and 63% at the respective inhibitor doses of 4 and 6 mg/mouse, respectively. The combined administration of topotecan and Tdp1 inhibitor is viewed as the most effective way to eliminate the metastatic formations with possible restitution of focal lesions.
Asunto(s)
Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Hidrolasas Diéster Fosfóricas/metabolismo , Topotecan/uso terapéutico , Animales , Carcinoma Pulmonar de Lewis/patología , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Hidrolasas Diéster Fosfóricas/metabolismo , Inhibidores de Topoisomerasa I/farmacología , Topotecan/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Teoría Cuántica , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Topotecan/síntesis química , Topotecan/químicaRESUMEN
The author name M. V. Edeeva should read M. V. Edeleva.
RESUMEN
Antimetastatic effect of the liposomal form of recombinant lactaptin RL2 (a proteolytic fragment of human breast milk κ-casein; 8.6 kDa) was studied in A/Sn mice after intravenous transplantation of GA-1 tumor with high rate of liver metastases. Tumor growth in the liver was found in all mice. In animals dying early, the tumors were presented by multiple nodes of about the same size; in mice dying later, the tumors in the liver were presented by just few large nodes formed by cells that survived chemotherapy. A single intravenous injection of RL2 lactaptin in liposomes prolonged lifespan of animals with liver metastases of GA-1 tumor by 1.5 times in comparison with that in untreated animals.
Asunto(s)
Antineoplásicos/farmacología , Caseínas/farmacología , Liposomas/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Composición de Medicamentos/métodos , Femenino , Humanos , Inyecciones Intravenosas , Liposomas/química , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Longevidad/efectos de los fármacos , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Proteínas Recombinantes/farmacología , Análisis de SupervivenciaRESUMEN
Effect of alkoxyamines on normal and tumor cells was studied in vitro and in vivo. In vitro experiments showed that alkoxyamines produce a dose-dependent toxic effect on cells of human breast tumor MCF7 line. Transplantation of Krebs-2 ascites carcinoma cells preincubated with alkoxyamines to mice did not induce tumor growth. An opposite effect was observed in normal mouse cells: functional activity of peritoneal macrophages increased. The possibility of using alkoxyamines as theranostic agents is discussed.
Asunto(s)
Antineoplásicos/farmacología , Hidroxilaminas/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/fisiología , Masculino , Ratones , Ratones Endogámicos CBA , Trasplante de Neoplasias , Fagocitosis/efectos de los fármacosRESUMEN
Antimetastatic activity of Platin in lyophilized liposomes stored for 7 years after fabrication was evaluated. The main flaw of liposomes as vehicles for drug delivery to the tumors is their high affinity for the liver, which accumulates a great amount thereof. This property of liposomes can be used for adjuvant therapy of operable primary tumors metastasizing to the liver. It is shown on the model of mouse GA-1 tumor metastases in the liver that platinum(II) complex compound Platin in phosphatidylcholine-cholesterol liposomes, stored for 7 years after lyophilization, causes complete cure of 40% animals, while free Platin prolongs the lifespan of mice with tumors by only 31.7% vs. control (no treatment).
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Liposomas/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos Organoplatinos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/mortalidad , Carcinoma de Ehrlich/patología , Colesterol/química , Esquema de Medicación , Composición de Medicamentos , Estabilidad de Medicamentos , Femenino , Liofilización , Inyecciones Intravenosas , Liposomas/química , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Ratones , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacocinética , Fosfatidilcolinas/química , Análisis de SupervivenciaRESUMEN
The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) were studied. The hydroxylating activity of liver microsomes of C57Bl/6Mv mice towards p-nitrophenol increased more than 4-fold 3 days after injection of TCPOBOP. Injection of diethylnitrosamine 3 days after TCPOBOP caused a lesser body weight loss and decrease of food consumption in C57Bl/6Mv mice than in response to diethylnitrosamine without preinduction. Injection of diethylnitrosamine to suckling ICR mice after TCPOBOP induction of cytochrome P450 2e1 activity led to development of 2-fold lesser number of tumors and pretumorous nodes in the liver in comparison with animals injected with diethylnitrosamine without induction. These data indicated that metabolism stimulation reduced the general toxic and hepatocarcinogenic effects of diethylnitrosamine.
Asunto(s)
Carcinogénesis/efectos de los fármacos , Inductores de las Enzimas del Citocromo P-450/farmacología , Dietilnitrosamina/metabolismo , Inactivación Metabólica/efectos de los fármacos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Piridinas/farmacología , Animales , Animales Lactantes , Peso Corporal/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Citocromo P-450 CYP2E1/metabolismo , Dietilnitrosamina/toxicidad , Hígado/efectos de los fármacos , Hígado/enzimología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/enzimología , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Nitrofenoles/metabolismo , Carga Tumoral/efectos de los fármacosRESUMEN
Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms.
Asunto(s)
Antineoplásicos/farmacología , Corticosterona/análogos & derivados , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias de los Músculos/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/farmacología , Compuestos Organoplatinos/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Corticosterona/farmacocinética , Corticosterona/farmacología , Sistemas de Liberación de Medicamentos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Liposomas/química , Liposomas/farmacocinética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Ratones , Neoplasias de los Músculos/mortalidad , Neoplasias de los Músculos/patología , Trasplante de Neoplasias , Compuestos de Mostaza Nitrogenada/farmacocinética , Compuestos Organoplatinos/farmacocinética , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/farmacología , Linfoma/tratamiento farmacológico , Paclitaxel/farmacología , Animales , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/toxicidad , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Apoptosis/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Ciclofosfamida/toxicidad , Interacciones Farmacológicas , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Masculino , Ratones , Ratones Endogámicos CBA , Trasplante de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Paclitaxel/toxicidadRESUMEN
In this paper in the bacterial Ames test we compared the mutagenicity of four aminoazo compounds, previously studied by other researchers and used for activation of rat liver enzymes, with the carcinogenicity in the rat liver. It was found that in the Ames test they have mutagenic activity, however, this activity does not correlate quantitatively with rat sensitivity to their hepatocarcinogenic action. Thus, the most active carcinogen 3'-methyl-4-dimethylaminoazobenzene causes mutations almost 2.5 times less than weakly carcinogenic ortho-aminoazotoluene, and exactly the same number of mutations as non-carcinogenic N,N-diethyl-4-aminoazobenzene.
Asunto(s)
Compuestos Azo/toxicidad , Carcinógenos/toxicidad , Mutágenos/toxicidad , Salmonella typhimurium/efectos de los fármacos , Animales , Hígado/efectos de los fármacos , Hígado/patología , Metildimetilaminoazobenceno/toxicidad , Mutación/efectos de los fármacos , Ratas , p-Aminoazobenceno/análogos & derivados , p-Aminoazobenceno/toxicidadRESUMEN
Experiments on male and female CC57BR/Mv mice differing by the sensitivity to carcinogenic effect of urethane on the lungs showed that castration 1 week before carcinogen challenge reduced the number of lung adenomas caused by it in males and somewhat increased the number of tumors in females. Exogenous testosterone after urethane injection caused virtually no changes in urethane effect in males and females. By contrast, elevation of testosterone concentrations in newborn male and female mice by injections or its decrease in feminized males receiving sodium glutamate during the neonatal period reduced the sensitivity to the carcinogenic effect of urethane in adult males and to its increase in females.
Asunto(s)
Carcinógenos/farmacología , Resistencia a Medicamentos , Pulmón/efectos de los fármacos , Uretano/farmacología , Virilismo/patología , Animales , Animales Recién Nacidos , Pruebas de Carcinogenicidad , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/efectos de los fármacos , Femenino , Pulmón/fisiología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/prevención & control , Masculino , Ratones , Embarazo , Caracteres SexualesRESUMEN
Ratio between proMMP and active MMP was studied in the dynamics of growth of the Lewis lung adenocarcinoma with lung metastasis. It was shown that tumor growth is associated with an increase in the content of proMMP (day 20; terminal stage), but the level of active MMP in tumor tissue did not signifi cantly change. The development of lung metastasis was accompanied by accumulation of active MMP (days 7, 15, and 20) and a decrease in the content of pro-MMP (days 7, and 20) in comparison with the control. In the spleen of these mice (metastasis-free organ), an increase in the levels of proMMP (day 20) and especially active MMP (days 7, 15, and 20) were found. The results suggest that tumor development shifts the proportion between active MMP and proenzymes in the tumor, lungs with metastasis, and spleen without metastasis.
Asunto(s)
Adenocarcinoma/enzimología , Carcinoma Pulmonar de Lewis/enzimología , Precursores Enzimáticos/metabolismo , Neoplasias Pulmonares/enzimología , Metaloproteinasas de la Matriz/metabolismo , Adenocarcinoma/secundario , Animales , Carcinoma Pulmonar de Lewis/secundario , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos CBA , Trasplante de Neoplasias , Carga TumoralRESUMEN
In this paper, the biological effects of diethylnitrosamine have been studied under controlled conditions of its metabolism in mice of different ages. The data presented indicate that diethylnitrosamine in a non-metabolized form exerts general toxic and hepatocarcinogenic effects while alkylating agents of this compound produce toxic liver injury. To our knowledge, the data presented impel to revise the general notion of an exceptional role of mutagenic activation in the carcinogenic effect of chemicals.
Asunto(s)
Alquilantes/toxicidad , Carcinogénesis/efectos de los fármacos , Dietilnitrosamina/toxicidad , Hígado/efectos de los fármacos , Alquilantes/administración & dosificación , Animales , Citocromo P-450 CYP2E1/efectos de los fármacos , Citocromo P-450 CYP2E1/metabolismo , Dietilnitrosamina/administración & dosificación , Humanos , Hígado/enzimología , Hígado/lesiones , Hígado/patología , Ratones , Mutágenos/administración & dosificaciónRESUMEN
Ethyl pyruvate, an inhibitor of indoleamine 2,3-dioxygenase, slightly suppressed the growth of transplantable Ehrlich tumor in mice and significantly potentiated the therapeutic effect of cyclophosphamide. Another inhibitor amidoxime produced a similar effect. However, both ethyl pyruvate and amidoxime significantly reduced the effect of cycloplatam therapy. The observed changes can be stipulated by different effects of cyclophosphamide and cycloplatam on the subpopulations of lymphoid cells taking part in the formation of antitumor immunity and resistance to tumors.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Ciclofosfamida/farmacología , Inhibidores Enzimáticos/farmacología , Compuestos Organoplatinos/farmacología , Oximas/farmacología , Piruvatos/farmacología , Animales , Carcinoma de Ehrlich/enzimología , Carcinoma de Ehrlich/inmunología , Carcinoma de Ehrlich/patología , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Inmunidad Innata/efectos de los fármacos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Carga Tumoral/efectos de los fármacosRESUMEN
The effects of ortho-aminoazotoluene on carcinogenic activity of diethylnitrosamine were studied in CBA and ICR mice. Injection of ortho-aminoazotoluene before and after diethylnitrosamine led to a significant reduction of its anticarcinogenic effect, judging from significantly lower level of liver tumors. Pentachlorophenol, inhibitor of sulfotransferase (catalyzing the terminal stage of ortho-aminoazotoluene metabolic activity), stimulated its carcinogenic effect on mouse liver. On the other hand, pentachlorophenol reduced the protective effect of ortho-aminoazotoluene on diethylnitrosamine-induced hepatocarcinogenesis in mice. Presumably, the carcinogenic and anticarcinogenic effects of ortho-aminoazotoluene were realized by its initial form or intermediate (non-sulfated) metabolites.
Asunto(s)
Anticarcinógenos/farmacología , Carcinogénesis/efectos de los fármacos , Neoplasias Hepáticas Experimentales/metabolismo , o-Aminoazotolueno/farmacología , Animales , Dietilnitrosamina , Femenino , Hígado/química , Hígado/enzimología , Hígado/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Masculino , Ratones Endogámicos CBA , Ratones Endogámicos ICR , Pentaclorofenol/farmacología , Sulfotransferasas/antagonistas & inhibidores , Sulfotransferasas/metabolismoRESUMEN
It is found that after administration of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB,) which was hepatocarcinogenic to rats, in suckling mice, the number of neoplastic lesions in the liver of mice was 3 times higher than after analogous administration of equimolar dose of ortho-aminoazotoluene (OAT)). However, in the Ames test (TA-98 strain of Salmonella typhimurium) with activation by hepatic enzymes (S-9 fraction) of both intact and Aroclor-1254-induced mice and rats OAT contributed by an order of magnitude to revertant colonies compared to 3'-Me-DAB. In vivo inhibition of sulfotransferase activity, the enzyme which catalyzes the final stage of the mutagenic activation of aminoazo dyes, had no effect on carcinogenicity of 3'-Me-DAB but more than 4 times elevated that of OAT. It was concluded that the mechanism of carcinogenic action of aminoazo dyes studied is not genotoxic and that the carcinogenic potential of OAT is lost in the process of mutagenic activation.
Asunto(s)
Carcinógenos/toxicidad , Colorantes/toxicidad , Neoplasias Hepáticas Experimentales , Metildimetilaminoazobenceno/toxicidad , Mutágenos/toxicidad , o-Aminoazotolueno/toxicidad , Animales , Carcinógenos/farmacología , Colorantes/farmacología , Hígado/enzimología , Hígado/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/enzimología , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/patología , Metildimetilaminoazobenceno/farmacología , Ratones , Ratones Endogámicos CBA , Ratones Endogámicos ICR , Mutágenos/farmacología , Ratas , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , o-Aminoazotolueno/farmacologíaRESUMEN
The modifying effect of the one compound on carcinogenicity of the other in the combined application is attributed usually to some changes in the carcinogen metabolism, i.e. its activation or inactivation. In this paper, when used separately, diethylnitrosamine (DENA) induced 4-6 times more neoplastic lesions in the liver of suckling mice than ortho-aminoazotoluene (OAT) did. However, after combined treatment with both carcinogens the total number of hepatic lesions was significantly lower than that in mice treated with DENA only. Similar effect was observed when OAT was administered 3 days before or 3 days after DENA injection. The observed protective effect is not mediated at metabolic level, because OAT has no effect on metabolism of DENA in mouse liver. Our findings can be unequivocally explained by the competition of the carcinogens for target protein molecules, presumably transcription factors, participating in hepatocyte differentiation, which differently interact with and are diversely impaired by different compounds.
Asunto(s)
Carcinógenos/farmacología , Dietilnitrosamina/efectos adversos , Neoplasias Hepáticas Experimentales , Proteínas de Neoplasias/metabolismo , o-Aminoazotolueno/efectos adversos , Alquilantes/efectos adversos , Alquilantes/farmacología , Animales , Animales Recién Nacidos , Colorantes/efectos adversos , Colorantes/farmacología , Dietilnitrosamina/farmacología , Antagonismo de Drogas , Femenino , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos CBA , Ratones Endogámicos ICR , o-Aminoazotolueno/farmacologíaRESUMEN
Indolamine-2,3-dioxygenase, a tryptophan-catabolizing enzyme, creates local conditions suppressing immune lymphocytes. Expression of this enzyme in tumors protects them from immune mechanisms, while its inhibition partially reduces tumor immunoresistance. This effect is attained by multiple subcutaneous or intraperitoneal injections of ethyl pyruvate, an indolamine-2,3-dioxygenase inhibitor. Experiments on mouse nonsyngenic tumor have demonstrated the immunomodulating effect of chronic oral ethyl pyruvate administered with drinking water.