RESUMEN
Toxicities of 5-fluoro-2'-deoxyuridine (FUdR) and its liposome incorporated dipalmitoyl derivative (FUdR-dipalmitate) to mouse bone marrow, spleen, liver and ileum were compared after treatment for 6 consecutive days. The applied doses of the two formulations, which were shown earlier to have equal antitumor activity in mouse tumor models, were 600 and 2 mumol/kg respectively. When applied in these doses, toxicity to the hemopoietic system, measured as a decreases in progenitor and precursor cells of the erythroid and granuloid/macrophage lineage in bone marrow and spleen, was more severe for FUdR than for liposomal FUdR-dipalmitate. In the liver, mitotic figures, as indicators of cell division, were absent for both drugs while in control livers the number of cells in mitosis was approximately 2%. Toxicity to the ileum was more severe for liposomal FUdR-dipalmitate than for FUdR and was manifested by granulocyte infiltration, the presence of cell debris, loss of columnar epithelial cells and enlarged nuclei with prominent nucleoli in these cells. Thus, by prolonging the retention time of FUdR in vivo, using liposomes as a vehicle and FUdR-dipalmitate as a lipophilic prodrug, the dose-limiting toxicity appears to shift from bone marrow to the gastrointestinal tract.
Asunto(s)
Antineoplásicos/toxicidad , Floxuridina/análogos & derivados , Profármacos/toxicidad , Animales , Antineoplásicos/administración & dosificación , Peso Corporal/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Portadores de Fármacos , Femenino , Floxuridina/administración & dosificación , Floxuridina/toxicidad , Íleon/efectos de los fármacos , Íleon/patología , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Liposomas , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Tamaño de los Órganos/efectos de los fármacos , Profármacos/administración & dosificación , Bazo/efectos de los fármacos , Bazo/patologíaRESUMEN
The antitumor effects of muramyl tripeptide phosphatidylethanolamine, incorporated within the lipophilic phase of liposomes (lipMTP-PE) were studied using a model of liver metastasis of colon cancer in the rat. Intravenous immunotherapy with lipMTP-PE, when started 2 days before the inoculation of tumor cells and given twice a week, significantly reduced subsequent tumor growth in the liver. The main effect of treatment appeared to be a substantial local increase in the number of tumoricidal macrophages and lymphocytes. Tumor cell lysis by isolated macrophages in vitro, however, appeared not to be elevated above the level triggered by tumor growth alone. Therefore, the observed therapeutic effect of lipMTP-PE probably results from a combination of (1) an increase in the number of cytotoxic macrophages at the onset of metastatic growth in the liver, thus increasing the probability of lethal contacts between tumoricidal effectors and tumor cells and (2) indirect effects of lipMTP-PE, via the induction of cytokine production by liver macrophages, leading to increased numbers and/or activity of cytotoxic lymphocytes and natural killer cells.
Asunto(s)
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Antineoplásicos/farmacología , Neoplasias del Colon/patología , Liposomas/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Fosfatidiletanolaminas/farmacología , Acetilmuramil-Alanil-Isoglutamina/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/secundario , Animales , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Citotoxicidad Inmunológica , Inmunohistoquímica , Inmunoterapia , Liposomas/química , Macrófagos/citología , Masculino , Ratas , Ratas Endogámicas , Células Tumorales CultivadasRESUMEN
The therapeutic effect of a combination of liposomal muramyl dipeptide (MDP) and 5-fluorouracil (5FU) was studied in a murine tumor model of hepatic metastases of the tumor cell line C26, a colon adenocarcinoma. Liposomal MDP (250 micrograms/kg body wt) and a low, nontoxic, dose of 5FU (10 mg/kg body wt) were mixed and administered during 6 consecutive days once daily, three times i.v. and three times i.p. Treatment was initiated 4 days after intrasplenic tumor cell injection. The combination of liposomal MDP and 5FU significantly reduced the number of liver metastases and the total tumor load in the liver. Liver weights of tumor-bearing mice treated with the combination were significantly lower than the liverweights of control mice (p < 0.005) and of mice treated with 5FU alone (p < 0.02) or liposomal MDP alone (p < 0.05). Liposomal MDP and 5FU, when given as single treatment modalities, had no significant effect on the number of metastases and liver weight. These results show that liposomal MDP can enhance the therapeutic effect of 5FU for the treatment of liver metastases.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Acetilmuramil-Alanil-Isoglutamina/administración & dosificación , Animales , Femenino , Fluorouracilo/administración & dosificación , Liposomas , Neoplasias Hepáticas Experimentales/secundario , Ratones , Ratones Endogámicos BALB C , Tamaño de los Órganos , Organismos Libres de Patógenos EspecíficosRESUMEN
In a reproducible murine model of liver metastases, it was demonstrated that liposomal muramyl dipeptide (MDP) as an adjuvant therapy reduces and prevents the development of metastases. C26 colon adenocarcinoma cells were injected into the spleen (5 x 10(4) cells per mouse) of syngeneic BALB/c mice. On day 3, the spleen was removed to prevent a large tumor burden in the spleen. On day 17, 100% of the mice had developed tumor foci in the liver. Liposomal MDP treatment consisted of the i.v. or i.p. administration of 1 mumol of liposomal lipid containing 5 micrograms of MDP per mouse for ten consecutive days. When therapy was initiated two days after tumor cell inoculation, the number of metastases that had developed on day 17 was strongly reduced compared to control mice. Approximately 20% of the mice were free of liver metastases. Initiation of therapy two days prior to tumor cell inoculation enhanced the effect significantly: about 45% of the mice were free of metastases on day 17. The treatment protocol for survival studies was slightly different; liposomal MDP was administered on the first six consecutive days followed by administration twice weekly, through day 24. Control mice died between day 21 and 33 after tumor cell inoculation, whereas liposomal MDP treated mice died between day 26 and 46 with 1 out of 25 mice surviving for more than 120 days. The mortality of the liposomal MDP treated mice that were free of liver metastases was caused by a local tumor at the site of operation.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Acetilmuramil-Alanil-Isoglutamina/uso terapéutico , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Acetilmuramil-Alanil-Isoglutamina/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/secundario , Animales , Neoplasias del Colon/patología , Femenino , Lípidos/análisis , Liposomas , Neoplasias Hepáticas Experimentales/secundario , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Tamaño de los Órganos/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Inhibition of mitochondrial protein synthesis impairs the formation of the 13 polypeptides encoded on the mitochondrial genome. These polypeptides are part of enzyme complexes involved in oxidative phosphorylation. Prolonged inhibition of mitochondrial protein synthesis thus reduces the oxidative phosphorylation capacity which ultimately results in impairment of energy-requiring processes. Via a different mechanism glucocorticoid hormones also decrease the oxidative phosphorylation capacity of, e.g., lymphoid cells. The present study shows that inhibition of mitochondrial protein synthesis influences glucocorticoid-induced responses of lymphoid cells in two opposing manners. (a) It is enhanced after induction in cells with a reduced oxidative phosphorylation capacity resulting from preceding inhibition of mitochondrial protein synthesis. This can be explained by the synergistic effects of glucocorticoids and prolonged inhibition of mitochondrial protein synthesis on energy-producing processes. (b) It is counteracted when mitochondrial protein synthesis is impaired during induction of the response. The latter observation suggests that mitochondrial protein synthesis is involved in the generation of glucocorticoid-induced effects on lymphoid cells.
Asunto(s)
Glucocorticoides/farmacología , Linfocitos/metabolismo , Mitocondrias/metabolismo , Biosíntesis de Proteínas , Inhibidores de la Síntesis de la Proteína/farmacología , Adrenalectomía , Animales , Peso Corporal/efectos de los fármacos , Dexametasona/farmacología , Doxiciclina/farmacología , Sinergismo Farmacológico , Metabolismo Energético , Humanos , Leucemia Experimental/patología , Linfocitos/efectos de los fármacos , Linfocitos/ultraestructura , Masculino , Mitocondrias/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Ratas , Ratas Endogámicas , Timo/anatomía & histología , Células Tumorales CultivadasRESUMEN
Inhibition of mitochondrial protein synthesis by doxycycline (DC), a tetracycline analogue, has significant antitumor effects in several tumor systems. In the present study, the effects of continuous DC treatment combined with intermittent administration of Adriamycin or 1-beta-D-arabinofuranosyl cytosine on the growth of a rat leukemia were investigated. The presence of DC retards tumor relapse after 1-beta-D-arabinofuranosyl cytosine or Adriamycin treatment significantly. DC may therefore be of value in several modalities of antitumor treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxiciclina/administración & dosificación , Leucemia Experimental/tratamiento farmacológico , Animales , Citarabina/administración & dosificación , Doxorrubicina/administración & dosificación , Masculino , RatasRESUMEN
It has been shown before that prolonged treatment with doxycycline (DC), an inhibitor of mitochondrial protein synthesis, leads to proliferation arrest of a leukemia in the rat and, moreover, to eradication of this tumor. It has also been demonstrated that the period of treatment required to achieve this is shorter when DC administration is started in later stages of tumor progression. Therefore, the leukemic cells may have properties with regard to DC sensitivity which change with time during tumor progression. In the present study this hypothesis was tested by studying the permeability for DC, the presence of cell-surface molecules, and the mitochondrial content of the leukemic cells in various stages of tumor development in control and in DC-treated rats. Changes in DC permeability or antigenic phenotype were not observed, but the content of mitochondria decreases during tumor progression. DC treatment leads to an additional reduction of the content of functional mitochondria which results in proliferation arrest. The higher mitochondrial content of the leukemic cells during the earlier stages of tumor development explains thus why a longer period of DC treatment is needed to achieve growth arrest when treatment is started in these stages.
Asunto(s)
Doxiciclina/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Mitocondrias/metabolismo , Biosíntesis de Proteínas , Animales , Antígenos de Neoplasias/análisis , Leucemia Experimental/metabolismo , Masculino , Permeabilidad , Fenotipo , RatasRESUMEN
The results described in this paper demonstrate that proliferation arrest by low concentrations of tetracyclines, which has previously been shown in experiments with animal tumor systems, can also be achieved in tumor systems of human origin. Tetracyclines specifically inhibit mitochondrial protein synthesis. Prolonged and continuous impairment of protein synthesis inside the mitochondria leads to reduction of the cellular concentration of the polypeptide products which are coded and synthesized within mitochondria. These products are part of the oxidative phosphorylative system of the cell. Long-term tetracycline treatment leads to a decrease of oxidative ATP-generating capacity as monitored by cytochrome c oxidase activity. This may cause severe energetic or metabolic disturbances which explain the proliferation arrest observed. Proliferation arrest, provided that mitochondrial protein synthesis is blocked effectively, is found in vitro as well as in vivo. It is shown that the effect of doxycycline is not limited to cytostasis; prolonged doxycycline treatment is clearly cytotoxic for the tumor cells.
Asunto(s)
Antineoplásicos , Doxiciclina/farmacología , Neoplasias Renales/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular , Doxiciclina/uso terapéutico , Esquema de Medicación , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Masculino , Ratones , Trasplante de Neoplasias , Biosíntesis de Proteínas , Ratas , Análisis EspectralRESUMEN
The tetracyclines specifically inhibit mitochondrial protein synthesis when present at the same low concentrations as used for their antibacterial action. Inhibition of mitochondrial protein synthesis leads to decrease in the oxidative energy-generating capacity of cells. Therefore, the presence of tetracyclines may result in proliferation arrest. In the present study we show that continuous intravenous administration of polyvinylpyrrolidone (PVP) induces the formation of granulomas in the normal rat liver; the rats usually die within 2 weeks of continuous PVP treatment. Athymic (nude) rats appear to be more resistent to the deleterious effects of PVP as they survive the treatment for at least 5 weeks. Although the livers of the PVP-treated nude rats are heavily infiltrated with phagocytic cells, they seldom show granulomas. Reconstitution of nude rats with syngenic thymocytes leads, on the other hand, to extensive granuloma formation. Normal rats treated continuously with PVP plus doxycycline, however, all survive, their livers showing only a few very small granulomas and the normal low number of phagocytic cells. We conclude that the formation of granulomas induced by PVP is a process which is mediated by T-lymphocytes. Because doxycycline prevents this kind of granuloma formation it seems likely that doxycycline not only impairs the proliferation and differentiation of T-lymphocytes but also of monocytes and macrophages.
Asunto(s)
Doxiciclina/uso terapéutico , Granuloma/prevención & control , Hepatopatías/prevención & control , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas , Granuloma/inducido químicamente , Granuloma/mortalidad , Granuloma/patología , Hígado/patología , Hígado/ultraestructura , Hepatopatías/mortalidad , Hepatopatías/patología , Microscopía Electrónica , Fagocitos/patología , Fagocitos/ultraestructura , Vehículos Farmacéuticos , Povidona , Ratas , Ratas EndogámicasRESUMEN
Previous studies showed that T-lymphoid cells are permeable to the tetracyclines, whereas B-lymphoid and erythroid cells are not. The tetracyclines impair mitochondrial protein synthesis if they have access to cells. Inhibition of mitochondrial protein synthesis during a number of cell cycles results, as a consequence, in proliferation arrest. The tetracyclines can therefore be considered as cytostatics. In the present study the effect of prolonged treatment with doxycycline on the growth of a T-cell type leukaemia of the rat was investigated. It is shown that doxycycline treatment inhibits not only tumour cell proliferation, but leads moreover to complete tumour eradication. The way by which the latter is achieved depends on the doxycycline concentration and, surprisingly, on the stage of tumour progression at which doxycycline administration is started. As, because of the permeability barrier, the proliferation of erythroid and B-lymphoid cells is not affected by the tetracyclines, the tetracyclines may provide a tool without serious side-effects in the therapy of T-type tumours.
Asunto(s)
Doxiciclina/uso terapéutico , Leucemia Linfoide/tratamiento farmacológico , Linfocitos T , Animales , Recuento de Células , División Celular , Doxiciclina/administración & dosificación , Cinética , Leucemia Linfoide/patología , Trasplante de Neoplasias , RatasRESUMEN
The mitochondrial genetic system is indispensable for the biosynthesis of the enzyme complexes involved in aerobic energy generation. Tetracyclines inhibit the expression of only the mitochondrial genes because they specifically block mitochondrial protein synthesis. A salient feature is that this inhibition occurs at the low concentration required for anti-bacterial treatment, provided that this concentration is maintained continuously. Evidence is presented that the growth of carcinogen-induced tumors can be inhibited by tetracyclines. It is further shown that the development in the cheek pouch of the Syrian hamster of a transplantable hypernephroma from human origin can be strongly retarded by tetracyclines as well. Therefore, the mitochondrial genetic system has to be reckoned as a target for chemotherapy and tetracyclines as cytostatic agents.
Asunto(s)
Antineoplásicos/uso terapéutico , Genes/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Tetraciclinas/uso terapéutico , Animales , Carcinoma de Células Renales/tratamiento farmacológico , Cricetinae , Doxiciclina/administración & dosificación , Evaluación Preclínica de Medicamentos , Femenino , Neoplasias Renales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Mesocricetus , Metilnitrosourea , Trasplante de Neoplasias , Oxitetraciclina/administración & dosificación , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Large unilamellar liposomes (50 to 500 mumol of lipid per kg) were injected i.v. or i.p. into normal and lymphosarcoma-bearing mice. The percentage of the dose remaining in the blood and that accumulated in liver, spleen, and various other organs was measured 4 hr after injection. The results indicate that liposomes cause a dose-dependent saturation of the hepatic and splenic clearance capacities. One day after injection of 10(6) lymphosarcoma cells, the capacity of the tumor-bearing mice to eliminate liposomes from the blood (in a 4-hr period) was inhibited 30 to 50%. This could be ascribed to a decreased activity of the reticuloendothelial system caused by the tumor cells, as was indicated by the simultaneous inhibition of carbon clearance. Six days after injection of the lymphosarcoma cells, the elimination of liposomes from the blood in tumor-bearing mice was restored to the value in normal mice. The possible involvement of tumor cells in the uptake of liposomes by the liver was investigated morphologically after i.v. injection of peroxidase-containing liposomes into lymphosarcoma-bearing mice. Liposome-entrapped peroxidase activity was never observed in the tumor cells. The results presented here indicate that the lymphosarcoma cells do not directly participate in the hepatic accumulation of liposomes, although their mere presence may have significant indirect effects on the elimination of liposomes from the blood and on their tissue distribution.
Asunto(s)
Liposomas/administración & dosificación , Animales , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Liposomas/metabolismo , Hígado/metabolismo , Linfoma no Hodgkin , Ratones , Ratones Endogámicos C57BL , Distribución TisularRESUMEN
Oxytetracycline was given by means of chronic i.v. infusion, in amounts which impair specifically mitochondrial protein synthesis, to Wistar rats carrying a solid Leydig cell tumor. The prolonged inhibition of mitochondrial protein synthesis finally results in proliferation arrest of the s.c. growing tumor. As long as the tumor is growing, the energy-generating capacity of the mitochondrial becomes diluted, until it is reduced to a critical level, which results in growth arrest. This cytostatic effect is found after treatment for 8 to 12 days. During this period, the tumor volume increases to an extent comparable to 2 to 3 tumor cell divisions. The proliferation arrest found is, at least after treatment for 3 weeks, reversible. Withdrawal of oxytetracycline results in continuation of tumor growth after a latent period of about 5 days. The data confirm previous observations made in experimental systems about the usefulness of mitochondrial protein synthesis as target for cancer chemotherapy. They support, moreover, the explanation given for the marked prolongation of survival time found in tetracycline-treated patients with a squamous cell carcinoma of the larynx-pharynx. If antineoplastic therapy, based on inhibition of mitochondrial protein synthesis, is considered, the tetracyclines should be the drugs of choice, because their toxic side effects are minimal at dosages which cause tumor proliferation arrest.
Asunto(s)
Tumor de Células de Leydig/metabolismo , Proteínas de Neoplasias/biosíntesis , Neoplasias Testiculares/metabolismo , Animales , Tumor de Células de Leydig/patología , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Trasplante de Neoplasias , Neoplasias Experimentales/metabolismo , Neoplasias Hormono-Dependientes/metabolismo , Oxitetraciclina/farmacología , Ratas , Ratas Endogámicas , Neoplasias Testiculares/patologíaRESUMEN
The proliferation of Zajdela tumor cells, grown in vivo in Wistar rats, is arrested by low amounts of oxytetracycline. Oxytetracycline is administered by means of continuous infusion in such a way that the oxytetracycline concentration in serum and ascitic fluid is maintained at a level at which only mitochondrial protein synthesis is blocked. Under these conditions, Zajdela mitochondrial tumor cells cease dividing after a few cell generations, an event which is preceded by reduction of cytochrome c oxidase activity of the tumor cells. Toxicity to host tissues is limited to the immune system which is apparently suppressed by the drug. Even so, oxytetracycline might have therapeutic potential in human cancer therapy, especially because it does not influence the hemopoietic system.