RESUMO
Despite its effectiveness as an antineoplastic drug, doxorubicin (DOX) is usually associated with cardiotoxicity. Lovastatin (LOV), a hypolipidemic agent used in the clinic, has been demonstrated to have antitumoral and antimetastatic effects in murine models. Since the two agents arrest tumor cells in different phases of the cell cycle and induce apoptosis, the goal of this study was to examine the efficacy of a combination therapy with LOV and low doses of DOX, in an attempt to obtain an improved antitumoral effect devoid of toxicity, by using a rat B-cell lymphoma and a mouse mammary tumor. In the two models, the combined treatment showed a synergistic antitumoral effect, which is mainly ascribed to an increased apoptotic response elicited by a LOV/DOX combination than either agent alone. The therapeutic benefit demonstrated by the combination treatment is further emphasized by the lack of toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Doxorrubicina/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , RatosRESUMO
Concomitant antitumoral resistance (CAR), the phenomenon by which the growth of distant secondary tumor implants or metastases in some tumor-bearing hosts is inhibited by the presence of a primary tumor, has been previously ascribed to an antiangiogenic process. Here, we investigated vascular endothelial growth factor (VEGF) and endostatin serum levels in nude or BALB/c mice bearing human lung tumors (Calu-6 and H460) or murine mammary tumors (M3MC, M-234p and M-234m), respectively. In these experimental models we previously found an association between in vivo generation of CAR and in vitro conversion of plasminogen into angiostatin. Serum endostatin level in CAR+ Calu-6-bearing mice was significantly higher than in CAR- H460 counterpart. Sera from mammary tumor-bearing mice showed similar levels of endostatin, regardless of their ability to induce CAR. Conversely, serum VEGF levels in mice bearing CAR+ tumors were lower than those found in CAR- tumor-bearing hosts. Immunostaining with an anti-CD31 antibody revealed that secondary tumors subjected to CAR were significantly less vascularized than primary tumors, while this difference was not observed in CAR- tumors. In vitro studies showed an inhibitory effect of sera from CAR-inducing tumors on endothelial cell proliferation as compared to normal sera, whereas sera from non-CAR-inducing tumors did not alter endothelial proliferation and, in some instances, even caused stimulation of endothelial proliferation. These data suggest that the antiangiogenic mechanism operating in concomitant antitumoral resistance is the result of an increase in the ratio of antiangiogenic/proangiogenic regulators. The levels of the factors involved in this phenomenon can vary in the different tumor models, but the trend favoring the inhibition of angiogenesis is always conserved.
Assuntos
Adenocarcinoma/patologia , Inibidores da Angiogênese/fisiologia , Proteínas Angiogênicas/fisiologia , Neoplasias Pulmonares/patologia , Neoplasias Mamárias Experimentais/patologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/fisiopatologia , Adenocarcinoma/sangue , Angiostatinas/sangue , Angiostatinas/fisiologia , Animais , Linhagem Celular Tumoral , Células Cultivadas/efeitos dos fármacos , Endostatinas/biossíntese , Endostatinas/sangue , Endostatinas/fisiologia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Mamárias Experimentais/sangue , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/sangue , Transplante de Neoplasias , Plasminogênio/metabolismo , Transplante Heterólogo , Transplante Homólogo , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
The aim of this report was to investigate the feasibility of systemic treatment of transitional cell carcinoma of the bladder with vinflunine (VFL), and to compare its activity in respect to vinorelbine (VRL). Exposure of MB49 murine bladder cancer cells to both drugs showed a higher chemosensitivity of the cells to VRL than to VFL (IC50 values of 60 nM and 400 nM, respectively). Pretreatment of MB49 cells with non-cytotoxic drug concentrations revealed an inhibition of control in vitro invasiveness of 40 to 70% (1-25 nM VRL) and 22 to 80% (1-100 nM VFL) (P < 0.0001, ANOVA). The intraperitoneal administration of the drugs twice a week for 4 weeks in C57B1/6 female mice revealed that VFL was very well tolerated, with a 8-fold increase in the maximum tolerated dose in respect to VRL (40 mg/kg and 4.8 mg/kg, respectively). The administration schedule was evaluated in C57B1/6 female mice inoculated transurethraly with 5 x 10(4) MB49 cells. Intravesical tumor incidence on day 21 was 0% and 17% in mice treated intraperitoneally with 20 and 10 mg/kg VFL respectively (P = 0.0017 and P = 0.0001, Fischer's Exact Test), contrasting with 75-83% obtained in all VRL-treated groups and Controls. All mice treated with 20 mg/kg VFL were still alive 60 days after intravesical MB49 tumor implantation, as well as 50% of those treated with 10 mg/kg VFL, while most of the remaining mice (Control and VRL-treated) died before day 32. These studies clearly demonstrate the activity of VFL against a murine bladder cancer model, with a favorable toxicity profile.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Vimblastina/análogos & derivados , Vimblastina/uso terapêutico , Animais , Carcinoma de Células de Transição/patologia , Divisão Celular/efeitos dos fármacos , Esquema de Medicação , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/patologia , Vimblastina/administração & dosagem , VinorelbinaRESUMO
The phenomenon by which tumor-bearing hosts are capable of inhibiting secondary tumor implants or metastases, known as concomitant antitumoral resistance (CAR), is presumably due to antiangiogenesis at places distant from the primary tumor. Although angiostatin, a potent inhibitor of angiogenesis, has been reported to be one of the factors responsible for suppressing the growth of secondary tumors in mice bearing previous tumors, it has not been definitively proven yet. With the aim of investigating whether CAR-inducing cancer cells display a differential angiostatin production and to support the role ascribed to that molecule concerning the inhibition of secondary tumor implants, 5 tumor models with different CAR-inducing capacities were studied herein. One of the 2 human lung cancer cell lines analyzed revealed a strong CAR against secondary s.c. tumor implants in nude mice, and 2 of 3 of the murine mammary tumors used exhibited inhibitory effect on secondary s.c. and i.v. tumor inoculations in syngeneic hosts. Since angiostatin is a proteolytic fragment from plasminogen, we examined by Western blot the ability of all conditioned media collected from the tumor cells studied to convert plasminogen to angiostatin. An association between in vivo generation of CAR and in vitro conversion of plasminogen into angiostatin was found. Since different enzymatic mechanisms were described to explain the generation of angiostatin, we also studied gelatinase and urokinase-type plasminogen activator secretion in conditioned media by zymography. The conversion of plasminogen into angiostatin by conditioned media was mainly inhibited by broad-spectrum serine proteinase inhibitors, suggesting a possible role for 1 or more enzymes of that group in the process. These findings suggest the existence of a differential angiostatin generation by CAR-inducing cancer cells, providing additional support to previous data obtained by other authors.