RESUMO
Although several tumour types express both AT1 and AT2 angiotensin II receptors, and angiotensin II stimulates cell proliferation, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are not effective anti-cancer agents. Development of a biologically active monoclonal antibody (6313/G2) against the AT1 receptor prompted the testing of a recombinant short-chain variable fragment form (R6313/G2) against breast cancer cells in vitro and in vivo. Cell lines MCF-7, MDA-MB-231 and T47D all expressed both receptor subtypes. In vitro, R6313/G2 suppressed cell proliferation in the presence of 100 nM angiotensin II, with IC50s of 30 nM, 153 nM and 2.8 microM for the three cell types respectively; in contrast, the AT1 receptor blocker losartan was effective only in T47D cells, at 25 microM. Studies on MCF-7 and T47D cells showed R6313/G2 also opposed the angiotensin II-induced inhibition of caspase-3/7 activity. In vivo, hollow fibres containing the cell lines were implanted in nu/nu balb-c mice at two sites, s.c. and i.p. Treatments of R6313/G2 at 2.5 nmol/kg and 25 nmol/kg twice per day for 7 days dose dependently reduced cell numbers for all three cell lines, but here MCF-7 cells responded most sensitively and MDA-MB-231 cells least. Although T47D cells were refractory at the s.c. site, growth was inhibited at the i.p. location, and otherwise results were similar at the two sites. In xenografts, MCF-7 cell tumours were dose dependently reduced by R6313/G2, and 13 and 27 nmol/kg R6313/G2 twice/day gave means of 74 and 76% tumour regression after 7 days. The data suggest that the anti-cancer action of R6313/G2 is considerably more effective than AT1 antagonists.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Receptor Tipo 1 de Angiotensina/imunologia , Receptor Tipo 2 de Angiotensina/imunologia , Proteínas Recombinantes/uso terapêutico , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Animais , Apoptose , Determinação da Pressão Arterial , Western Blotting , Neoplasias da Mama/metabolismo , Caspases/metabolismo , Sobrevivência Celular , Feminino , Humanos , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/imunologia , Losartan/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Células Tumorais Cultivadas , Vasoconstritores/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: to evaluate the role of Triclosan (Irgasan(R)) in the prevention of prosthetic graft infection. MATERIAL AND METHODS: fifty-one pigs were assigned randomly to six groups. Group I (graft) and II (graft and Triclosan) were control groups. Groups III (graft) and IV (grafts and Triclosan) were contaminated with 2 x 10(7)CFU/ml S. aureus. Groups V (graft) and VI (graft and Triclosan) were intraoperatively contaminated with 2 x 10(7)CFU/ml S. aureus and reoperated on after 7 days. Remaining animals were sacrificed on day 28. The end point of the investigation was vascular graft infection, defined as the bacteriological and/or histological proof of infection. Results in both control groups no vascular graft infections were detected in Groups I and II. All of the group III animals presented but none of the group IV developed a graft infection (p <0.02). All of the group V animals presented and 10 of 12 animals developed a graft infection. CONCLUSION: in this animal model Triclosan bonding appears effective in preventing prosthetic graft infection. However, the in situ replacement of Triclosan-protected grafts was not successful in the treatment of graft infection.