RESUMEN
Neither immunologic nor genetic concepts of carcinogenesis have yet been decisively confirmed, and epigenetic theories, as formulated so far, are either non-predictive or insufficiently consistent with morphologic and experimental evidence. Computing data, concerned with carcinogenic mechanisms and neoplastic changes at the level of the endoplasmic reticulum, may lead to a new coherent understanding of tumor pathogenesis. Carcinogenic agents initiate biophysical perturbations, chemical alterations and conformational transitions in the membrane lattice of the endoplasmic reticulum. Foremost among the resulting neoplastic changes is an increased, irreversible separation of polyribosomes from membranes of the ergastoplasm. The carcinogenic process, apparently, deletes a protein required for polysome attachment. Since microsomal cytochromes can be synthesized by membrane-bound polysomes only, the translation of genetic information for their biosynthesis is irreversibly restricted. A similar, self-perpetuating deficiency may be postulated for the polysome attachment protein. Activities, depending on cytochromes P-450 and b5, are hampered, e.g. those of the monoxygenase system. Cholesterogenesis is derepressed. Ratios of phospholipids/cholesterol are decreased, and lipid-protein complexes, altered both in structure and function. Another distinct effect of the membrane-polysome separation is the unmasking of thiol-disulfide exchange enzymes which, in turn, stimulate the biosyntehsis of proteins and of deoxyribonucleotides involved in cell replication.
Asunto(s)
Microsomas/fisiología , Neoplasias/etiología , Animales , Carcinógenos , Gatos , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos/metabolismo , Retículo Endoplásmico/metabolismo , Radicales Libres , Cobayas , Metabolismo de los Lípidos , Neoplasias Hepáticas Experimentales , Ratones , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Neoplasias/inducido químicamente , Polirribosomas/ultraestructura , RatasRESUMEN
Macromolecular dextrans carrying substituents terminated by sulfhydryl groups or terminated by aromatic amines effectively inhibit the growth of a fibrosarcoma and of a mammary adenocarcinoma in a syngeneic mouse model. These compounds have no or very low toxicity to animals and are nontoxic to fibrosarcoma cells in vitro. Small-molecular-weight compounds carrying the same substituents as the above dextrans are without any effect on the growth of these tumors. A dextran substituted with mercury-containing side chains is growth promoting for the same fibrosarcoma in mice at doses which are nontoxic for these animals. However, the mercury-containing compound is toxic to fibrosarcoma cells in vitro. It is hypothesized that these nonpermeating macromolecules do not directly influence the tumor cells in animals but modulate the natural system of defense against tumors; cells of that system are stimulated or poisoned by the substituted dextrans.
Asunto(s)
Antineoplásicos , Dextranos/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Sarcoma Experimental/tratamiento farmacológico , Animales , Células Cultivadas , Masculino , Mercurio/farmacología , Ratones , Ratones Endogámicos C3H , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/farmacologíaAsunto(s)
Retículo Endoplásmico/metabolismo , Neoplasias Experimentales/metabolismo , Carcinógenos/metabolismo , Colesterol/metabolismo , Citocromos/metabolismo , Transporte de Electrón , Retículo Endoplásmico/enzimología , Retículo Endoplásmico/ultraestructura , Inducción Enzimática , Radicales Libres , Metabolismo de los Lípidos , Proteínas de la Membrana/metabolismo , Microsomas/metabolismo , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/ultraestructura , Polirribosomas/metabolismo , Compuestos de Sulfhidrilo/metabolismoRESUMEN
Nonimmunological defenses are very diverse in type. Some are directed against already transformed cells and belong to mechanisms of containment. Others exert a surveillance by preventing or inhibiting initial events of carcinogenesis. Chalones and oncolytic factors in sera and exudates are agents of containment. Under appropriate circumstances, the autoxidation of thiols and the formation of mixed disulfides lead to destruction of tumor cells in vitro and in vivo. Both processes involve the generation of superoxide radicals and of hydrogen peroxide which, in turn, activate the peroxide:peroxidase:halide system. Thiol:disulfide ratios and interchange codetermine the antioxidative activity of cellular membranes, thus bearing on carcinogenesis. Many aliphatic and aromatic antioxidants are endowed with anticarcinogenic properties. The fact that they are inhibitors of free radical processes corroborates the increasingly evident role of free radicals in carcinogenesis. Endogenous antioxidants and exogenous ones in foods are agents of surveillance. Antioxidant activity, linked with the ergastoplasm, points to a homeostatic mechanism that prevents self-accelerating chain reactions from leading to membrane damage or to carcinogenesis. Carcinogens can also be inactiviated by microsomal enzymes belonging to an overall mechanism of detoxification. Activity levels of these systems depend on diet and state of nutrition. They may be naturally very low, but they can be increased with various inducers.
Asunto(s)
Líquido Ascítico/análisis , Neoplasias/fisiopatología , Animales , Antioxidantes/farmacología , Línea Celular , Células Cultivadas , Disulfuros/metabolismo , Exudados y Transudados , Ácidos Grasos Insaturados/farmacología , Femenino , Glutatión Peroxidasa/metabolismo , Inhibidores de Crecimiento/metabolismo , Inhibidores de Crecimiento/fisiología , Halógenos/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Metabolismo de los Lípidos , Lipoproteínas HDL/fisiología , Masculino , Mercaptoetilaminas/farmacología , Ratones , Ratones Endogámicos , Microsomas/enzimología , Neoplasias/sangre , Neoplasias/metabolismo , Neoplasias Experimentales/metabolismo , Neutrófilos/metabolismo , Compuestos Organotiofosforados/farmacología , Oxidación-Reducción , Peroxidasas/metabolismo , Embarazo , Protectores contra Radiación/farmacología , Selenio/farmacología , Compuestos de Sulfhidrilo/metabolismoRESUMEN
In experimental animals, a systemic treatment with thiols of the mercaptoalkylamine type has affected all of five solid tumors so far investigated. (Three of the tumors were transplanted into the strain of origin.) There was either inhibition of growth or "oncodieresis," i.e., a necrosis and sloughing of tumors conducive to full recovery and repair. Mercaptoalkylamines and derivatives of the type used in our experiments are known to bind to cellular sites by a two-point attachment involving both thiol and amino groups. One of these compounds, cysteamine, was active in its native, unsubstituted form, but did not bring about oncodieresis when either the amino or thiol group, or both, were alkylated. Mercaptopropylamine, the 3-carbon homolog of cysteamine, was less active. Cystamine, a disulfide dimer of cysteamine that has no free reactive sulfhydryl, did not induce any reaction. Thioglycerol, lacking a terminal amino group, had only negligible activity. Rejection was much more striking when treatment was started on the day of inoculation than when started 7 days later. Male mice rejected better than females. Results were inferior when tow of the agents were given simultaneously or together with other radioprotectants, such as L-cysteine, glutathione, dimethyl sulfoxide, or reserpine. Tumor rejection was enhanced when the phosphorylated thioyls, S-2-(3-aminopropylamino)ethylphosphorothioic acid or S-(2-ethylguanidine)phosphorothioci acid, were given simultaneously with the radioprotective serotonin, but there was no synergy of serotonin with the nonphosphorylated compounds S-2-aminoethylisothiouronium bromide or cysteamine. Serotonin alone did not affect the tumors.