RESUMO
BACKGROUND: The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings. METHODS: Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 µg Dz13, in a 50 µL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers. FINDINGS: Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated. INTERPRETATION: Dz13 was safe and well tolerated after single intratumoral injections at all doses. FUNDING: Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Basocelular/tratamento farmacológico , DNA Catalítico/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , DNA Catalítico/efeitos adversos , DNA Catalítico/farmacocinética , Feminino , Humanos , Injeções Intralesionais , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Percutaneous transluminal coronary angioplasty is a frequently used interventional technique to reopen arteries that have narrowed because of atherosclerosis. Restenosis, or renarrowing of the artery shortly after angioplasty, is a major limitation to the success of the procedure and is due mainly to smooth muscle cell accumulation in the artery wall at the site of balloon injury. In the present study, we demonstrate that the antiangiogenic sulfated oligosaccharide, PI-88, inhibits primary vascular smooth muscle cell proliferation and reduces intimal thickening 14 days after balloon angioplasty of rat and rabbit arteries. PI-88 reduced heparan sulfate content in the injured artery wall and prevented change in smooth muscle phenotype. However, the mechanism of PI-88 inhibition was not merely confined to the antiheparanase activity of this compound. PI-88 blocked extracellular signal-regulated kinase-1/2 (ERK1/2) activity within minutes of smooth muscle cell injury. It facilitated FGF-2 release from uninjured smooth muscle cells in vitro, and super-released FGF-2 after injury while inhibiting ERK1/2 activation. PI-88 inhibited the decrease in levels of FGF-2 protein in the rat artery wall within 8 minutes of injury. PI-88 also blocked injury-inducible ERK phosphorylation, without altering the clotting time in these animals. Optical biosensor studies revealed that PI-88 potently inhibited (Ki 10.3 nmol/L) the interaction of FGF-2 with heparan sulfate. These findings show for the first time the capacity of this sulfated oligosaccharide to directly bind FGF-2, block cellular signaling and proliferation in vitro, and inhibit injury-induced smooth muscle cell hyperplasia in two animal models. As such, this study demonstrates a new role for PI-88 as an inhibitor of intimal thickening after balloon angioplasty. The full text of this article is available online at http://www.circresaha.org.
Assuntos
Angioplastia com Balão/efeitos adversos , Músculo Liso Vascular/efeitos dos fármacos , Oligossacarídeos/farmacologia , Túnica Íntima/efeitos dos fármacos , Animais , Ligação Competitiva , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/prevenção & controle , Divisão Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Heparitina Sulfato/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Oligossacarídeos/metabolismo , Coelhos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Média/efeitos dos fármacos , Túnica Média/metabolismo , Túnica Média/patologia , Tempo de Coagulação do Sangue TotalRESUMO
Worldwide, one in three cancers is skin-related, with increasing incidence in many populations. Here, we demonstrate the capacity of a DNAzyme-targeting c-jun mRNA, Dz13, to inhibit growth of two common skin cancer types-basal cell and squamous cell carcinomas-in a therapeutic setting with established tumors. Dz13 inhibited tumor growth in both immunodeficient and immunocompetent syngeneic mice and reduced lung nodule formation in a model of metastasis. In addition, Dz13 suppressed neovascularization in tumor-bearing mice and zebrafish and increased apoptosis of tumor cells. Dz13 inhibition of tumor growth, which required an intact catalytic domain, was due in part to the induction of tumor immunity. In a series of good laboratory practice-compliant toxicology studies in cynomolgus monkeys, minipigs, and rodents, the DNAzyme was found to be safe and well tolerated. It also did not interfere in more than 70 physiologically relevant in vitro bioassays, suggesting a reduced propensity for off-target effects. If these findings hold true in clinical trials, Dz13 may provide a safe, effective therapy for human skin cancer.