RESUMEN

Sheep are becoming increasingly important in medical research. The objective of the present study was to identify changes in bioactivity of fluoxetine during ruminal passage in ewes, and to examine the effects of fluoxetine administration on demeanor and serum prolactin concentration. Twelve mature ewes were administered saline (control), daily oral fluoxetine (40 mg), or alternate-day oral fluoxetine for 10 d. Four additional ewes were fitted with rumen cannulas and administered daily fluoxetine by abomasal deposition. Serum samples were collected daily for 15 d. Serum fluoxetine concentrations (ELISA) were greater (P < 0.001) in ewes in all fluoxetine treatments compared with controls on d 2. Serum fluoxetine concentrations in ewes receiving daily abomasal dosages were greater (P < 0.007) than those in controls on d 2 to 12 and were greater than those in ewes receiving daily or alternate-day oral fluoxetine on d 3 to 12. Serum prolactin concentration (RIA) did not differ (P = 0.137) among treatments and was only weakly correlated with serum fluoxetine concentration (r = 0.20, P = 0.041), and regression analysis revealed that very little variation in serum prolactin concentration was due to serum fluoxetine concentration (R(2) = 0.04, P = 0.082). Demeanor ratings on d 1 to 12 remained at normal in all treatment groups (P > 0.362). However, in ewes that had received an abomasal dosage of fluoxetine, demeanor scores decreased (P < 0.029) on d 13 and 14 before returning to normal on d 15 (P = 0.397). This study indicates that mature ewes may provide a suitable model for the study of fluoxetine, but that a larger oral dosage may be required relative to the human dosage to overcome partial loss of bioactivity during ruminal passage.

Asunto(s)

Conducta Animal/efectos de los fármacos , Fluoxetina/farmacología , Fluoxetina/farmacocinética , Prolactina/sangre , Rumen/fisiología , Ovinos , Animales , Disponibilidad Biológica , Vías de Administración de Medicamentos , Esquema de Medicación , Fluoxetina/administración & dosificación , Fluoxetina/sangre , Motilidad Gastrointestinal , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología

RESUMEN

Reliable cell-based assays and animal models have been developed for evaluating agents against hepatitis B virus. Although much progress has been made, in vitro and in vivo assays for hepatitis C virus are still on the horizon. Advances towards establishing inexpensive and reliable experimental models have accelerated the development of therapeutic modalities for these life-threatening viral infections. The characterization of well-defined viral targets coupled with improved molecular diagnostic technologies have illuminated this field.

Asunto(s)

Modelos Animales de Enfermedad , Hepacivirus/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Animales , Antivirales/farmacología , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Hepacivirus/genética , Hepatitis B/virología , Virus de la Hepatitis B/genética , Hepatitis C/virología , Humanos , Pruebas de Sensibilidad Microbiana

RESUMEN

We employed the Rauscher murine leukemia virus (RMuLV) as a murine retrovirus model of AIDS, to test biological response modifiers (BRM) and antiviral agents for potential therapeutic activity against the human immunodeficiency virus (HIV). We examined the relationship between the augmentation of natural killer (NK) cell activity and antiviral efficacy of a series of BRM, most of which are known inducers of interferon, in this model. Poly [I,C]-LC, MVE-2, and CL 246,738, but not Ampligen, soluble glucan, or 7-thia-8-oxoguanosine, consistently produced antiviral activity. In addition, the combination of suboptimal doses of oral 3'-azido-3'-deoxythymidine (AZT) (in drinking water) and poly [I,C]-LC produced a synergistic antiviral effect. With all the BRM tested, a consistent pattern emerged, namely that antiviral activity always correlated with the augmentation of splenic NK cell activity in infected animals. For instance, poly [I,C]-LC boosted NK activity much more in infected mice treated therapeutically (treatment initiated after infection) than prophylactically (treatment initiated before infection), and it had greater antiviral activity therapeutically than prophylactically. For the BRM tested, antiviral activity did not occur without augmentation of NK activity in infected mice. In contrast, augmentation of NK activity in uninfected mice bore no relationship to antiviral activity. Furthermore, elimination of NK cells by treating mice with anti-asialo GM1 abolished the antiviral activity of poly [I,C]-LC. Although splenic NK activity was ablated by anti-asialo GM1, serum interferon levels were not affected by this treatment. These results point to a causal connection between the augmentation of NK cell activity and the antiviral efficacy of these BRM in this murine AIDS model. NK cells thus appear to play a key role in resistance to this retrovirus, as has been suggested for HIV.

Asunto(s)

Síndrome de Inmunodeficiencia Adquirida/inmunología , Factores Inmunológicos/farmacología , Células Asesinas Naturales/fisiología , Zidovudina/farmacología , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Acridinas/farmacología , Acridinas/uso terapéutico , Animales , Anticuerpos/farmacología , Antivirales/farmacología , Antivirales/uso terapéutico , Asialoglicoproteínas/inmunología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Gangliósido G(M1)/inmunología , Glucanos/farmacología , Glucanos/uso terapéutico , Guanosina/análogos & derivados , Guanosina/farmacología , Guanosina/uso terapéutico , Factores Inmunológicos/uso terapéutico , Técnicas In Vitro , Células Asesinas Naturales/efectos de los fármacos , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Poli I-C/farmacología , Poli I-C/uso terapéutico , Poli U/farmacología , Poli U/uso terapéutico , Copolímero del Pirano/farmacología , Copolímero del Pirano/uso terapéutico , Conejos , Virus Rauscher/inmunología , Organismos Libres de Patógenos Específicos , Ensayo de Placa Viral , Zidovudina/uso terapéutico

RESUMEN

Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polypeptides in cultures of human T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1) and therefore suppress the infectivity of HIV-1 in vitro. We have previously reported the antiviral activity in vitro of HIV-1 protease inhibitors against the C-type retrovirus Rauscher murine leukemia virus (RMuLV) and the lentivirus simian immunodeficiency virus (SIV). The same compounds which blocked the infectivity of HIV-1 also inhibited the infectivity of RMuLV and SIV in vitro. This report extends these findings by testing the antiviral activity of HIV-1 protease inhibitors in vivo in the RMuLV model. RMuLV-infected mice were treated twice a day (bid) with either an active (SKF 108922) or inactive (SKF 109273) compound for fourteen days by the intraperitoneal (i.p.) route. Compared with excipient control, SKF 108922, formulated with hydroxypropyl-beta-cyclodextrin (HPB), reduced virus-induced splenomegaly, viremia, and serum reverse transcriptase (RT) levels, while SKF 109273 was inactive. The HPB vehicle by itself enhanced replication of RMuLV. The effects of changing the formulation and the route of administration were examined. SKF 108922, formulated in HPB, had similar antiviral activity when administered by the i.p. or subcutaneous (SC) routes. However, SKF 108922 administered as a colloidal suspension in cholesterol sulfate (CS) had no detectable antiviral effect. Measurements of the circulating levels of the protease inhibitor in plasma explained this result. Plasma concentrations of SKF 108922 exceeded 1000 nM within 10 min after SC administration of the compound solubilized in HPB, but SKF 108922 was not detected in plasma after SC administration of the same dose formulated with CS. Information on optimal conditions for administering these agents should prove useful in guiding their clinical application Therefore, RMuLV should provide a good model for the preclinical evaluation and development of this class of agents for the treatment of HIV.

Asunto(s)

Antivirales/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Virus Rauscher/efectos de los fármacos , Infecciones por Retroviridae/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológico , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Animales , Antivirales/sangre , Antivirales/farmacocinética , Línea Celular , Ciclodextrinas/farmacología , Femenino , Inhibidores de la Proteasa del VIH/sangre , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Leucemia Experimental/virología , Ratones , Ratones Endogámicos BALB C , Oligopéptidos/sangre , Oligopéptidos/farmacocinética , Vehículos Farmacéuticos/farmacología , ADN Polimerasa Dirigida por ARN/sangre , Infecciones por Retroviridae/virología , Infecciones Tumorales por Virus/virología

RESUMEN

The mechanism of therapeutic activity for recombinant murine interferon-gamma (rMu IFN gamma) in the treatment of metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the tumor-bearing organ) were tested after 1 week and 3 weeks of rMu IFN gamma administration (i.v. three times per week). Natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocyte (CTL) activities against specific and nonspecific targets, and macrophage tumoristatic activity were measured. rMu IFN gamma demonstrated immunomodulatory activity in most assays of immune function. The optimal therapeutic protocol of rMu IFN gamma (2.5 x 10(6) U/kg, three times per week) prolonged survival and decreased the number of pulmonary metastatic foci. This therapeutic activity was correlated with specific CTL activity from pulmonary parenchymal mononuclear cells (PPMC), but not from spleen or blood. Macrophage tumoristatic activity in PPMC also correlated with therapeutic activity, but activity in alveolar macrophages did not. However, therapeutic activity did not correlate with NK or LAK activity at any site. These results demonstrate that the optimal therapeutic protocol is the same as the optimal immunomodulatory dose for pulmonary CTL and macrophage activities. Furthermore, while immunological monitoring may help to optimize treatment protocols, current monitoring procedures that use readily accessible sites, particularly peripheral blood, may not accurately predict the therapeutic efficacy of biological response modifiers in clinical trials.

Asunto(s)

Interferón gamma/uso terapéutico , Macrófagos/inmunología , Neoplasias Experimentales/terapia , Linfocitos T Citotóxicos/inmunología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Interferón gamma/farmacología , Células Asesinas Activadas por Linfocinas/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/inmunología , Proteínas Recombinantes , Linfocitos T Citotóxicos/efectos de los fármacos , Células Tumorales Cultivadas

Asunto(s)

Adyuvantes Inmunológicos/farmacología , Carboximetilcelulosa de Sodio/farmacología , Factores Inmunológicos/farmacología , Células Asesinas Naturales/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Murino/tratamiento farmacológico , Poli I-C/farmacología , Polilisina/farmacología , Zidovudina/farmacología , Animales , Antivirales/farmacología , Sinergismo Farmacológico , Inductores de Interferón/farmacología , Células Asesinas Naturales/inmunología , Ratones , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/microbiología , Virus Rauscher/efectos de los fármacos

RESUMEN

Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polyproteins in cultures of human immunodeficiency virus type 1 (HIV-1)-infected T lymphocytes and, as a result, inhibit the infectivity of HIV-1 for such cultures. The ability of HIV-1 protease inhibitors to suppress replication of the C-type retrovirus Rauscher murine leukemia virus (R-MuLV) and the HIV-related lentivirus simian immunodeficiency virus (SIV) was examined in plaque reduction assays and syncytium reduction assays, respectively. Three of seven compounds examined blocked production of infectious R-MuLV, with 50% inhibitory concentrations of < or = 1 microM. Little or no cellular cytotoxicity was detectable at concentrations up to 100 microM. The same compounds which inhibited the infectivity of HIV-1 also produced activity against SIV and R-MuLV. Electron microscopic examination revealed the presence of many virions with atypical morphologies in cultures treated with the active compounds. Morphometric analysis demonstrated that the active compounds reduced the number of membrane-associated virus particles. These results demonstrate that synthetic peptide analog inhibitors of retroviral proteases significantly inhibit proteolytic processing of the gag polyproteins of R-MuLV and SIV and inhibit the replication of these retroviruses. These results are similar to those for inhibition of HIV-1 infectivity by these compounds, and thus, R-MuLV and SIV might be suitable models for the in vivo evaluation of the antiretroviral activities of these protease inhibitors.

Asunto(s)

Antivirales/farmacología , Virus de la Leucemia Murina/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Retroviridae/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Western Blotting , Línea Celular , Técnicas de Cultivo , Humanos , Microscopía Electrónica , Ensayo de Placa Viral , Proteínas Virales/biosíntesis , Proteínas Virales/metabolismo

RESUMEN

We examined the immunomodulatory and therapeutic activities of poly(I,C)-LC. Mice received a subcutaneous (s.c.) injection of sufficient numbers of MBL-2 lymphoma cells to produce in 1 week either a high or low tumor burden. A week after tumor cell injection, poly(I,C)-LC treatment was initiated; the agent was administered intraperitoneally (i.p.) at 5 mg/kg twice a week or at 2.5 or 0.5 mg/kg every day or as an intravenous (i.v.) injection at 0.5, 0.05, or 0.005 mg/kg three times a week. Poly(I,C)-LC treatment significantly increased antitumor effector cell functions in a variety of organs (including spleen, lungs, and peritoneum), as shown by increased killing of MBL-2 cells in vitro and increased tumor cell killing by natural killer cells and macrophages. Furthermore, prolongation of survival correlated with peritoneal macrophage tumoricidal activity when poly(I,C)-LC was given i.p. and with pulmonary effector cell function (including natural killer, cytolytic T-lymphocyte and macrophage tumoricidal activity) when the agent was administered i.v.

Asunto(s)

Carboximetilcelulosa de Sodio/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Poli I-C/uso terapéutico , Polilisina/uso terapéutico , Animales , Carboximetilcelulosa de Sodio/administración & dosificación , Carboximetilcelulosa de Sodio/farmacología , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Células Asesinas Naturales/efectos de los fármacos , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Neoplasias Experimentales/inmunología , Poli I-C/administración & dosificación , Poli I-C/farmacología , Polilisina/administración & dosificación , Polilisina/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos

Asunto(s)

Antivirales/toxicidad , Actividad Motora/efectos de los fármacos , Neurotoxinas/toxicidad , Reflejo de Sobresalto/efectos de los fármacos , Zalcitabina/toxicidad , Estimulación Acústica , Animales , Antivirales/uso terapéutico , Peso Corporal/efectos de los fármacos , Perros , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Haplorrinos , Leucemia Experimental/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Conejos , Ratas , Ratas Endogámicas , Virus Rauscher

RESUMEN

Murine acquired immunodeficiency syndrome (MAIDS) develops when C57B1/6 mice are inoculated with LP-BM5 murine leukemia viruses. Disease progression in these animals is characterized by lymphadenopathy, polyclonal B-cell activation, severe immunodeficiency, and death. Mice with MAIDS have been used to examine the efficacy of antiretroviral therapies for possible use in AIDS patients. In the present work, MAIDS mice were employed to test the hypothesis that established retroviral infection might be cured by the combined use of a cytotoxic agent (cyclophosphamide) and total body irradiation--a regimen reported to have successfully cured HIV-1 infection in one AIDS patient. Results indicate that the ablation of retrovirus-infected lymphoid cells reduced but did not eliminate LP-BM5 infection. Moreover, this regimen was no more effective at controlling virus proliferation or preventing the polyclonal IgG activation characteristic of murine AIDS than was AZT alone.

Asunto(s)

Ciclofosfamida/farmacología , Virus de la Leucemia Murina/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Murino/tratamiento farmacológico , Replicación Viral/efectos de los fármacos , Irradiación Corporal Total , Zidovudina/farmacología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/efectos de la radiación , Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Femenino , Virus de la Leucemia Murina/efectos de la radiación , Leucemia Experimental/tratamiento farmacológico , Leucemia Experimental/microbiología , Leucemia Experimental/radioterapia , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Síndrome de Inmunodeficiencia Adquirida del Murino/microbiología , Síndrome de Inmunodeficiencia Adquirida del Murino/radioterapia , Replicación Viral/efectos de la radiación , Zidovudina/uso terapéutico

RESUMEN

The Rauscher murine leukemia retrovirus system provides an in vivo model of the human acquired immune deficiency syndrome for testing the ability of antiviral agents and biological response modifiers (BRM) to suppress viremia and retroviral disease. In the present report we examined three agents in the Rauscher retrovirus model: imexon, Ampligen and poly[I,C]-LC. Imexon reduced splenomegaly, viremia, and serum reverse transcriptase levels even when treatment was not initiated until 7 days after virus infection. Imexon also significantly prolonged the survival of infected mice. Thus it proved to be an effective antiviral agent in this system, although imexon did not completely eliminate retroviral infection in treated mice. Poly[I,C]-LC and Ampligen had immunomodulatory effects. Both of these BRM augmented the cytolytic activity of splenic natural killer (NK) cells in infected animals when treatment was initiated 24 h after infection. Poly[I,C]-LC had antiretroviral activity when administered on this schedule. In order to examine the role of NK cell augmentation in the antiviral activity of poly[I,C]-LC, we attempted to deplete NK activity by treatment with rabbit antibody to asialo GM1, a ganglioside on the surface of murine NK cells. Combined treatment of infected mice with poly[I,C]-LC and anti-asialo GM1 decreased the antiviral activity of poly[I,C]-LC. This finding suggests that NK cells may be involved in the antiviral effect of this BRM.

Asunto(s)

Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Hexanonas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Virus Rauscher , Síndrome de Inmunodeficiencia Adquirida/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Leucemia Experimental/inmunología , Ratones , Ratones Endogámicos BALB C

RESUMEN

Bestatin is a potent inhibitor of aminopeptidase B, an enzyme which is found in abundance in the membrane of monocytes and macrophages. Binding of Bestatin to cells in the histiocytic linage upregulates colony stimulating activity (both in vitro and in vivo), which subsequently increases hematopoietic and hematologic values. We report that the treatment of mice with Bestatin upregulates the frequency and absolute numbers of colony forming unit--granulocyte-macrophage (CFU-GM), as well as the entry of CFU-GM into S phase (a measure of progenitor cell activity). As a result, there is an increase in bone marrow cellularity in cyclophosphamide myelosuppressed mice and an increase in the absolute neutrophil count in normal and myelosuppressed mice. The therapeutic application of this hematopoietic modulator has been demonstrated in combination cyclophosphamide and Bestatin protocols. While Bestatin has significant therapeutic activity for minimal metastatic disease, therapy models in which the hosts have greater metastatic tumor burdens requires combination chemoimmunotherapy for a significant therapeutic effect. Because myelosuppression as a therapeutic indication for Bestatin has only recently been recognized, few clinical studies have been undertaken with appropriate surrogates of hematopoietic activity. However, the preliminary clinical evidence of hematopoietic activity by this non-toxic dipeptide, as reviewed here, suggests that this may be an appropriate drug for the treatment of myelosuppressed patients. Thus, Bestatin as an orally active biological response modifier (BRM) has significant therapeutic activity for metastatic disease via multiple mechanisms including hematopoietic stimulation and macrophage activating properties.

Asunto(s)

Antibióticos Antineoplásicos/farmacología , Enfermedades de la Médula Ósea/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Leucina/análogos & derivados , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapéutico , Enfermedades de la Médula Ósea/inducido químicamente , Enfermedades de la Médula Ósea/inmunología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/farmacología , Quimioterapia Combinada , Femenino , Células Madre Hematopoyéticas/efectos de los fármacos , Leucina/administración & dosificación , Leucina/farmacocinética , Leucina/farmacología , Leucina/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/secundario , Ratones , Ratones Endogámicos C57BL

RESUMEN

Bestatin is a potent inhibitor of aminopeptidase, an enzyme found in abundance in the membrane of monocytes and macrophages. Following binding of bestatin to cells in the histiocytic lineage, the production of colony stimulating activity is upregulated (both in vitro and in vivo) with subsequent increases in hematopoietic and hematologic parameters. We report that the frequency and absolute numbers of CFU-GM as well as entry of CFU-GM into S phase (a measure of progenitor cell activity) is upregulated by treatment of animals with bestatin. This results in an increase in bone marrow cellularity in cyclophosphamide suppressed mice and an increase in the absolute neutrophil count in normal and suppressed mice. The therapeutic application of this hematopoietic modulator has been demonstrated in combination cyclophosphamide and bestatin therapeutic protocols. Because this indication for bestatin has only recently been recognized, few clinical studies have been undertaken utilizing appropriate surrogates of hematopoietic activity. However, preliminary clinical evidence of hematopoietic activity by this non-toxic dipeptide, as reviewed here, suggests that this may be an appropriate strategy for the treatment of myelosuppressed patients.

Asunto(s)

Aminopeptidasas/antagonistas & inhibidores , Médula Ósea/inmunología , Ciclofosfamida/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Tolerancia Inmunológica/efectos de los fármacos , Leucina/análogos & derivados , Animales , Recuento de Células/efectos de los fármacos , Ciclofosfamida/uso terapéutico , Quimioterapia Combinada , Leucina/farmacología , Leucina/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/secundario , Ratones

Asunto(s)

Antivirales/uso terapéutico , Hexanonas/uso terapéutico , Cetonas/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Infecciones por Retroviridae/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Femenino , Hexanonas/administración & dosificación , Factores Inmunológicos/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Virus Rauscher , Inhibidores de la Transcriptasa Inversa , Esplenomegalia/tratamiento farmacológico , Viremia/tratamiento farmacológico

RESUMEN

Pretreatment of mice with recombinant murine (rM) colony-stimulating factor-granulocyte-macrophage (CSF-gm) or recombinant human (rH) CSF-g provides partial protection from the lethal effects of ionizing radiation or the alkylating agent cyclophosphamide (CTX). In addition, these agents can significantly prolong survival if administered following lethal doses of irradiation or CTX. To induce protective activity, cytokines were injected 20 hours before lethal irradiation or CTX administration. To accelerate recovery from lethal irradiation, the cytokines must be administered shortly following irradiation, and the induction of maximal levels of activity is dependent on chronic administration. In contrast, because of their longer half-lives, accelerated recovery from alkylating agents requires a delay of at least 24 to 48 hours to allow complete clearance of CTX before administration of a CSF. Studies quantitating peripheral blood leukocytes and bone marrow cellularity as well as colony-forming units per culture (CFU-C) frequency and CFU-C per femur revealed a significant correlation between these parameters and the ability to survive lethal irradiation. This is a US government work. There are no restrictions on its use.

Asunto(s)

Factores Estimulantes de Colonias/uso terapéutico , Sustancias de Crecimiento/uso terapéutico , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Trasplante de Médula Ósea , Ensayo de Unidades Formadoras de Colonias , Factores Estimulantes de Colonias/administración & dosificación , Factores Estimulantes de Colonias/farmacocinética , Ciclofosfamida/toxicidad , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Sustancias de Crecimiento/administración & dosificación , Sustancias de Crecimiento/farmacocinética , Hematopoyesis/efectos de los fármacos , Inyecciones Intraperitoneales , Cinética , Leucopenia/inducido químicamente , Leucopenia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Quimera por Radiación , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico

RESUMEN

Bestatin has significant therapeutic activity (even following oral administration) for the treatment of metastatic disease, an activity which is limited by tumor burden. Therefore, the therapeutic potential of bestatin was examined in combination with chemotherapy to determine if there is additive activity for heavy tumor burdens. Bestatin significantly increased therapeutic activity and decreased the myelotoxicity of cyclophosphamide following a single injection of cyclophosphamide or split daily doses. In immune function studies, in tumor-bearing animals, bestatin increased the number of colony-forming units (granulocyte-macrophage) (CFU) and alveolar macrophage tumoricidal activity. However, when bestatin was combined with cyclophosphamide, which depressed bone marrow and macrophage activity, it did not show apparent augmentation of macrophage and NK cell activity, but did significantly increase bone marrow CFU activity. Thus, in combined chemoimmunotherapy, bestatin appears to enhance therapeutic activity by accelerating the recovery of hematopoiesis. We suggest, therefore, that a combination chemotherapy protocol, with oral bestatin, may facilitate myelorestoration following aggressive chemotherapy. The majority of biological response modifiers require parental administration; thus, the identification of an orally active, synthetic immunoaugmenting agent with a defined receptor is of particular interest.

Asunto(s)

Ciclofosfamida/uso terapéutico , Leucina/análogos & derivados , Metástasis de la Neoplasia , Neoplasias Experimentales/terapia , Adyuvantes Inmunológicos , Animales , Terapia Combinada , Citotoxicidad Inmunológica , Inmunidad Celular , Células Asesinas Naturales/inmunología , Leucina/uso terapéutico , Linfoma/terapia , Macrófagos/inmunología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/patología

RESUMEN

Human rIL-1 alpha and -1 beta are shown to increase significantly the CFU-culture activity in the spleen as well as at other sites after i.v. or i.p. administration. IL-1 can also significantly increase survival and can "rescue" a number of animals if administered either before or after lethal doses of cyclophosphamide or gamma-irradiation. The protective and reconstitutive activities of the rIL-1 are shown to correlate with increased CFU-culture frequency and total number, as well as increased cellularity in the bone marrow and peripheral blood, suggesting that this is one of their mechanisms of action. The sequence and timing of administration of human rIL-1 is critical for the protection or rescue of animals receiving DNA-damaging agents; maximal activity is achieved when IL-1 is given 20 h before insult or 48 h after alkylating agent administration. Minimal therapeutic activity is observed with IL-1 as a single agent for the treatment of metastatic disease compared with other biologic response modifiers including IFN-gamma.

Asunto(s)

Médula Ósea/efectos de los fármacos , Modelos Animales de Enfermedad , Células Madre Hematopoyéticas/efectos de los fármacos , Interleucina-1/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Animales , Células de la Médula Ósea , Ciclofosfamida/toxicidad , Esquema de Medicación , Femenino , Humanos , Interleucina-1/administración & dosificación , Cinética , Dosificación Letal Mediana , Leucopenia/inducido químicamente , Leucopenia/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Neoplasias Experimentales/tratamiento farmacológico , Traumatismos Experimentales por Radiación/mortalidad , Traumatismos Experimentales por Radiación/prevención & control , Proteínas Recombinantes/administración & dosificación

RESUMEN

The mechanism of therapeutic activity of recombinant murine interferon-gamma (rMu IFN-gamma) and the IFN inducer polyinosinic-polycytidylic acid solubilized with poly-L-lysine in carboxy methyl cellulose (pICLC) in treating metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the organ with tumor) were tested after 1 and 3 weeks of rMu IFN-gamma or pICLC administration (intravenous, three times a week). In these studies, natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocytes (CTL) (against specific and nonspecific targets), and macrophage tumoricidal and tumoristatic activities were measured. rM IFN-gamma and pICLC had therapeutic activity and immunomodulatory activity in most assays of immune function examined. Specific CTL activity of pulmonary parenchymal mononuclear cells (PPMC), but not in splenocytes or peripheral blood lymphocytes (PBL), during week 3 and not during week 1, correlated with the therapeutic activity of rMu IFN-gamma and of pICLC. Macrophage tumoricidal activity in PPMC, but not in alveolar macrophages, also correlated with the therapeutic activity of rMu IFN-gamma, but the opposite was true for the therapeutic activity of pICLC. NK activity of PPMC, but not of splenocytes or PBL, during week 1 correlated with the therapeutic activity of pICLC; in contrast, NK activity at any site did not correlate with the therapeutic activity of rMu IFN-gamma. LAK activity at any site did not correlate with the therapeutic activity of either agent.

Asunto(s)

Inductores de Interferón/farmacología , Interferón gamma/farmacología , Melanoma Experimental/patología , Animales , Inductores de Interferón/uso terapéutico , Interferón gamma/uso terapéutico , Células Asesinas Naturales/inmunología , Neoplasias Pulmonares/secundario , Linfocinas/inmunología , Macrófagos/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Linfocitos T Citotóxicos/inmunología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/inmunología , Células Tumorales Cultivadas/patología

Asunto(s)

Factores Estimulantes de Colonias/uso terapéutico , Interferón gamma/uso terapéutico , Interleucina-2/uso terapéutico , Melanoma Experimental/patología , Metástasis de la Neoplasia , Proteínas Recombinantes/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéutico , Animales , Inmunoterapia , Melanoma Experimental/terapia , Ratones

RESUMEN

It appears that the cytokines have significant therapeutic potential as an adjunct to established therapeutic regimens. It appears that, as single agents, they will have minimal therapeutic activity. However, in minimal residual disease settings or after debulking regimens by surgery, chemotherapy, or radiotherapy, significantly increased therapeutic activity can be expected by the addition of cytokines to treatment protocols.

Asunto(s)

Inmunoterapia , Melanoma Experimental/patología , Metástasis de la Neoplasia , Animales , Interferón gamma/uso terapéutico , Interleucina-2/uso terapéutico , Interleucina-3/uso terapéutico , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Proteínas Recombinantes/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéutico