RESUMEN
BACKGROUND: Patients diagnosed with metastatic cancer have almost uniformly poor prognoses. The treatments available for patients with disseminated disease are usually not curative and have side effects that limit the therapy that can be given. A treatment that is selectively toxic to tumors would maximize the beneficial effects of therapy and minimize side effects, potentially enabling effective treatment to be administered. METHODS AND FINDINGS: We postulated that the tumor-tropic property of stem cells or progenitor cells could be exploited to selectively deliver a therapeutic gene to metastatic solid tumors, and that expression of an appropriate transgene at tumor loci might mediate cures of metastatic disease. To test this hypothesis, we injected HB1.F3.C1 cells transduced to express an enzyme that efficiently activates the anti-cancer prodrug CPT-11 intravenously into mice bearing disseminated neuroblastoma tumors. The HB1.F3.C1 cells migrated selectively to tumor sites regardless of the size or anatomical location of the tumors. Mice were then treated systemically with CPT-11, and the efficacy of treatment was monitored. Mice treated with the combination of HB1.F3.C1 cells expressing the CPT-11-activating enzyme and this prodrug produced tumor-free survival of 100% of the mice for >6 months (P<0.001 compared to control groups). CONCLUSIONS: The novel and significant finding of this study is that it may be possible to exploit the tumor-tropic property of stem or progenitor cells to mediate effective, tumor-selective therapy for metastatic tumors, for which no tolerated curative treatments are currently available.
Asunto(s)
Camptotecina/análogos & derivados , Metástasis de la Neoplasia/terapia , Animales , Secuencia de Bases , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Hidrolasas de Éster Carboxílico/genética , Hidrolasas de Éster Carboxílico/metabolismo , Línea Celular , Línea Celular Tumoral , Cartilla de ADN/genética , Células Madre Embrionarias/enzimología , Células Madre Embrionarias/trasplante , Humanos , Irinotecán , Ratones , Ratones SCID , Células Madre Multipotentes/enzimología , Células Madre Multipotentes/trasplante , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Trasplante de Neoplasias , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Neuroblastoma/secundario , Neuroblastoma/terapia , Profármacos/farmacocinética , Profármacos/uso terapéutico , Conejos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción Genética , Trasplante HeterólogoRESUMEN
Low-molecular-weight chromium-binding substance (LMWCr), also known as chromodulin, is a chromium-binding oligopeptide proposed to have a function in chromium transport and insulin signaling in mammals. In this work, LMWCr has been isolated and purified for the first time from non-mammalian sources: chicken and American alligator. Milligram quantities of the oligopeptide can be obtained from kilogram quantities of liver. The LMWCr's from both sources are asparatate- and glutamate-rich oligopeptides which possess multinuclear chromium assemblies. The composition and physical and spectroscopic properties of the avian and reptilian LMWCr's are extremely similar to those of their mammalian analogues, suggesting the multinuclear sites of the biomolecule from all three classes of animal possess very similar structures. The chicken and alligator oligopeptides may possess intrinsic phosphotyrosine phosphatase activity.
