RESUMO
PURPOSE: We examined the interaction between cyclophosphamide (CPA) and angiostatin (AS) on the growth of primary Lewis lung carcinoma (LLC) tumors and on the development of LLC pulmonary metastases. We studied the effects of AS and CPA on the stages of angiogenesis employing in vitro assays. METHODS: Primary tumor growth and pulmonary metastases were measured to evaluate the effects of treatment with AS alone, CPA alone or the combination of CPA and AS. We examined the effects of CPA plus AS on endothelial cell (HUVEC) survival, migration and tube formation. RESULTS: Combined treatment with CPA and AS did not significantly affect primary tumor growth when compared with CPA treatment alone. However, a significant decrease in the number of pulmonary metastases was observed following CPA plus AS treatment when compared with CPA treatment alone ( P<0.001). AS did not enhance CPA-mediated HUVEC cytotoxicity, and CPA failed to enhance AS-mediated inhibition of migration. However, tube formation was inhibited following combined treatment with CPA and AS when compared with either treatment alone. CONCLUSIONS: AS enhanced the antimetastatic effects of CPA without significantly influencing the effects of CPA on primary tumor growth. CPA plus AS inhibited tube formation, suggesting that interrupting specific steps in the angiogenesis process might be an effective approach to the treatment of subclinical distant metastases.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/análogos & derivados , Ciclofosfamida/farmacologia , Metástase Neoplásica/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Plasminogênio/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Angiostatinas , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/secundário , Movimento Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Modelos Lineares , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Plasminogênio/administração & dosagem , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/farmacologia , Método Simples-Cego , Células Tumorais Cultivadas/transplanteRESUMO
Ionizing radiation (IR) and radical oxygen intermediates (ROIs) activate the early growth response-1 (Egr1) promoter through specific cis-acting sequences termed CArG elements. Ad.Egr.TNF.11D, a replication-deficient adenoviral vector containing CArG elements cloned upstream of the cDNA for human recombinant TNF-alpha was used to treat human esophageal adenocarcinoma and rat colon adenocarcinoma cells in culture and as xenografts in athymic nude mice. Cisplatin, a commonly used chemotherapeutic agent, causes tumor cell death by producing DNA damage and generating ROIs. The present studies demonstrate induction of TNF-alpha production in tumor cells and xenografts treated with the combination of Ad.Egr.TNF.11D and cisplatin. The results show that the Egr1 promoter is induced by cisplatin and that this induction is mediated in part through the CArG elements. These studies also demonstrate an enhanced antitumor response without an increase in toxicity following treatment with Ad.Egr.TNF.11D and cisplatin, compared with either agent alone. Chemo-inducible cancer gene therapy thus provides a means to control transgene expression while enhancing the effectiveness of commonly used chemotherapeutic agents.
