RESUMO
The dynamics of growth-stimulating and cytotoxic activity of mouse peritoneal macrophages (PMo) in response to in vivo and in vitro bacillus Calmette-Guérin (BCG) or bestatin treatment was studied. It was shown that BCG and bestatin induce cytotoxicity in PMo, and that after the cytotoxic response strong growth-stimulating activity develops. PMo, rendered cytotoxic in vivo and afterwards cultivated in vitro, displayed the same switch from a cytotoxic to a growth-stimulating phase. These results suggest that the growth-stimulating phase is the obligatory PMo response to biological response modifiers (BRM) at least to BCG and bestatin. The growth rate of tumours, transplanted into mice during the cytotoxic phase of the response to BCG, was suppressed, whereas tumours transplanted during the growth-stimulating phase were stimulated. It appears that the development of a growth-stimulating phase after the cytotoxic phase of response to activation by BRM could be one of the reasons for the limited effectiveness of immunotherapy based on the application of macrophage activators.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Vacina BCG/uso terapêutico , Fatores Imunológicos/uso terapêutico , Leucina/análogos & derivados , Ativação de Macrófagos/fisiologia , Neoplasias Experimentais/terapia , Animais , Divisão Celular/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Técnicas In Vitro , Leucina/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologiaRESUMO
The synthetic peptide C-1-6 related to the central part of human interleukin 2 molecule (sequence 59-72; N- and C-modified) had been shown previously to inhibit cytotoxic activity of macrophages converting them to synthesis of growth factors. In this paper the effect of C-1-6 on growth of sarcoma 180 in mice was studied. C-1-6 significantly accelerated tumor growth having been injected into mice in dose 5 or 50 microg per animal since the 4th day after tumor cells transplantation. Supernatants of Mphi in vitro activated by C-1-6 (10 microg/ml) and injected into mice also accelerated significantly sarcoma mass diurnal increasing as compared to mice treated with supernatants of non-activated Mphi or activated with bacterial lipopolysaccharide. A single injection of C-1-6 into mice either at the day or at the next day of tumor cells inoculation increased significantly the number of vessels growing up to transplant, thus the forming of the vascular bed had preceded tumor volume enlargement.
Assuntos
Interleucina-2/química , Fragmentos de Peptídeos/farmacologia , Sarcoma 180/irrigação sanguínea , Sarcoma 180/patologia , Animais , Humanos , Interleucina-2/farmacologia , Masculino , Camundongos , Transplante de Neoplasias , Neovascularização Patológica , Fragmentos de Peptídeos/administração & dosagem , Cavidade PeritonealRESUMO
The effect of a modified peptide of the middle part of the human interleukin-2 molecule (C-1-6) on the growth of transplantable sarcoma 180 of mice was studied. C-1-6 injected intraperitoneally in the dose of 0.5, 5 and 50 micrograms 4 times every other day was shown to stimulate tumor growth and enhance angiogenesis induced by the tumor transplanted intracutaneously. Stimulation of tumor growth was most apparent when the agent was given late (on day 4) after transplantation. Supernatants of murine peritoneal macrophages activated by 1 microgram/ml solution of C-1-6 proved capable of stimulating tumor growth, too. It is suggested that the stimulating effect of C-1-6 on tissue regeneration be investigated.
Assuntos
Interleucina-2/química , Neovascularização Patológica/induzido quimicamente , Fragmentos de Peptídeos/farmacologia , Sarcoma 180/fisiopatologia , Animais , Feminino , Humanos , Camundongos , Sarcoma 180/irrigação sanguíneaAssuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Interações Medicamentosas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Metástase Neoplásica , Fatores de TempoAssuntos
Antineoplásicos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Inibidores do Crescimento , Heparina , Antagonistas de Heparina , Humanos , Mitógenos/antagonistas & inibidores , Neoplasias/irrigação sanguínea , Neoplasias Experimentais/irrigação sanguíneaRESUMO
Although the phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) are almost equipotent inducers of an inflammatory and hyperplastic response in NMRI mouse skin, TPA acts as a converting or complete and RPA as a non-converting or incomplete skin tumor promoter. Bearing in mind the converting effect of skin wounding and TGF beta, we have addressed the question of a relationship between conversion and stromal events. For this purpose we have compared the effects of TPA and RPA on dermal angiogenesis, hair regrowth and the expression of tenascin in NMRI mouse skin in vivo. In the reticular part of the dermis, shaving alone induced angiogenesis peaking at day 14, concomitant with hair regrowth. While TPA exhibited a stimulatory effect on both parameters, RPA suppressed shaving-induced angiogenesis and delayed the onset of hair regrowth. Whether this difference in the phorbol ester effects being consistent with the working hypothesis is critical for conversion, remains to be shown. In the papillary dermis, however, RPA was more potent than TPA in inducing vascularization and tenascin expression. The kinetics of both responses corresponded to the time course of hyperproliferation induced by the phorbol esters in the overlaying epidermis, i.e. may be related to promotion proper, rather than conversion.