RESUMEN
The asymmetric unit of the title compound, C(28)H(20)N(2)O(2)·0.5C(2)H(5)OH, contains two independent mol-ecules of 1,1'-[o-phenyl-enebis(nitrilo-methyl-idyne)]di-2-naphthol, denoted A and B, and one ethanol solvent mol-ecule. The hydr-oxy groups are involved in intra-molecular O-Hâ¯N hydrogen bonds influencing the mol-ecular conformations, which are slightly different in mol-ecules A and B, where the two bicyclic systems form dihedral angles of 51.93â (9) and 58.52â (9)°, respectively. In the crystal structure, a number of short inter-molecular Câ¯C contacts with distances of less than 3.5â Å suggest the existence of π-π inter-actions, which contribute to the stability of the crystal packing.
RESUMEN
The asymmetric unit of the title compound, C(25)H(25)NO(2), contains two independent mol-ecules. The crystal packing exhibits weak inter-molecular C-Hâ¯O, C-Hâ¯π and π-π inter-actions.
RESUMEN
Interferon-beta (IFN-beta) induces various antiproliferative activities. In solid tumor cells, IFN-beta inhibits cell cycle progression, which mainly occurs as S phase accumulation. The IFN-beta-induced cell cycle effect has been implicated in the antitumor effect of combinations of IFN-beta and chemotherapeutic drugs. In this report, we characterized the viability of various human tumor cells in vitro after combination treatment with IFN-beta protein and the chemotherapeutic drugs, cis-platinum (II) diamine dichloride (cisplatin), 5-fluorouracil (5-FU), paclitaxel (Taxol) and gemcitabine. IFN-beta could significantly potentiate the cytotoxicity of these chemotherapeutic drugs. The potentiating effect was observed after pretreatment of tumor cells with IFN-beta but did not require the constant presence of IFN-beta. The potentiating effect correlated with the sensitivity of the tumor cells to the IFN-beta-induced cytotoxicity. Furthermore, chemotherapeutic drugs also potentiated the cytotoxicity of IFN-beta. We conclude that the cell cycle effect per se did not determine the ability of IFN-beta to potentiate the cytotoxicity of chemotherapeutic drugs. We suggest that the combination of local IFN-beta gene therapy with chemotherapy could be an effective cancer treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/análogos & derivados , Interferón beta/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/patología , Carcinoma/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacología , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Sinergismo Farmacológico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Humanos , Interferón beta/administración & dosificación , Neoplasias Pulmonares/patología , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Neoplasias del Cuello Uterino/patología , GemcitabinaRESUMEN
Previously, we provided evidence that adenovirus-mediated interferon-beta (IFN-beta) gene therapy inhibits tumor formation and causes dramatic regression of established tumors in immunodeficient mice. We suggested that local IFN-beta gene therapy with adenoviral vectors could be an effective treatment for cancer. In this report, the actions of murine IFN-beta (MuIFN-beta) gene delivery on both subcutaneous and metastatic tumors were evaluated in syngeneic immunocompetent mice. We found that the antitumor response mediated by MuIFN-beta gene delivery relied on CD8(+) T cells but was completely independent of CD4(+) T cells. In fact, depletion of CD4(+) T cells appeared to enhance the effect on tumor inhibition and animal survival induced by adenovirus-MuIFN-beta gene delivery. Therefore, adenovirus-MuIFN-beta gene therapy can bypass CD4(+) T helper (Th) cells and activate an effective CD8(+) T cell-dependent antitumor immunity in immunocompetent mice. Furthermore, we found that depletion of macrophages but not natural killer (NK) cells suppressed the antitumor response induced by MuIFN-beta gene therapy. These data, together with our previous results, suggest that in the clinical setting, local adenovirus-mediated IFN-beta gene therapy may lead to an efficient and long-lasting eradication of tumors by a direct antitumor effect and via activation of the innate and the adoptive immune systems.
Asunto(s)
Linfocitos T CD4-Positivos , Terapia Genética , Interferón beta/genética , Interferón beta/uso terapéutico , Neoplasias Experimentales/terapia , Adenoviridae/genética , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular , Femenino , Vectores Genéticos , Interferón beta/administración & dosificación , Depleción Linfocítica , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Neoplasias Experimentales/genética , Análisis de SupervivenciaRESUMEN
Interferon-beta (IFN-beta) induces aberrant cell cycle progression as well as cytotoxicity and apoptosis. However, the relationship between the cell cycle alteration and the induction of cytotoxicity/apoptosis is unknown. Here, we report the first demonstration that the IFN-beta-induced direct cytotoxic/apoptotic effect can be separated functionally from its cell cycle effect. By using lentiviral transduction, we generated human tumor cells that stably expressed IFN-beta and were resistant to its direct cytotoxic/apoptotic effect. Despite this resistance to apoptosis, these cells showed significant S phase accumulation as measured by both FACS analyses and bromodeoxyuridine (BrdU) incorporation. Although the cells proliferated in the presence of high levels of IFN-beta, they had lost their tumorigenicity in mice. A portion of these cells was observed to undergo a tumor cell-specific senescence. Therefore, our study revealed a direct tumor-suppressor function of IFN-beta. This tumor-suppressor function was independent of IFN-beta-induced direct cytotoxic effect. It was also distinct from the IFN-beta-induced immunologic antitumor response, an indirect effect of IFN-beta. We conclude that the antiproliferative effect on human tumor cells is the collective activities of the direct cytotoxic/apoptotic effect, the cell cycle alteration that occurs as predominantly S phase accumulation, and less frequently other cell cycle effects, such as G(1) arrest, and the promotion of tumor cells into a senescent-like state.