RESUMO
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by a microangiopathy and fibrosis of the skin and internal organs. No treatment has been proved to be efficient in case of early or advanced SSc to prevent or reduce fibrosis. There are strong arguments for a key role of topo-I in the pathogenesis of diffuse SSc. Irinotecan, a semisynthetic derivative of Camptothecin, specifically target topo-I. This study was undertaken to evaluate the effects of noncytotoxic doses of irinotecan or its active metabolite SN38 on collagen production in SSc fibroblasts. Dermal fibroblasts from 4 patients with SSc and 2 healthy donors were cultured in the presence or absence of irinotecan or SN38. Procollagen I release was determined by ELISA and expression of a panel of genes involved in fibrosis was evaluated by qRT-PCR. Subcytotoxic doses of irinotecan and SN38 caused a significant and dose-dependent decrease of the procollagen I production in dermal fibroblasts from SSc patients, respectively - 48 ± 3%, p < 0.0001 and - 37 ± 6.2%, p = 0.0097. Both irinotecan and SN38 led to a global downregulation of genes involved in fibrosis such as COL1A1, COL1A2, MMP1 and ACTA2 in dermal fibroblasts from SSc patients (respectively - 27; - 20.5; - 30.2 and - 30% for irinotecan and - 61; - 55; - 50 and - 54% for SN38). SN38 increased significantly CCL2 mRNA level (+ 163%). The inhibitory effect of irinotecan and its active metabolite SN38 on collagen production by SSc fibroblasts, which occurs through regulating the levels of expression of genes mRNA, suggests that topoisomerase I inhibitors may be effective in limiting fibrosis in such patients.
Assuntos
Fibroblastos/efeitos dos fármacos , Irinotecano/farmacologia , Pró-Colágeno/genética , Escleroderma Sistêmico/genética , Inibidores da Topoisomerase I/farmacologia , Actinas/genética , Actinas/metabolismo , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I/antagonistas & inibidores , Cadeia alfa 1 do Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Irinotecano/análogos & derivados , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Cultura Primária de Células , Pró-Colágeno/antagonistas & inibidores , Pró-Colágeno/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Pele/metabolismo , Pele/patologiaRESUMO
INTRODUCTION: Co-stimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibits T-cell activation. Clinically, CTLA-4 has been targeted in opposite ways: its blockade enhances antitumor immunity in the field of oncology, whereas CTLA-4 agonists such as abatacept are used for the treatment of immuno-inflammatory diseases as rheumatoid arthritis (RA). OBSERVATION: We herein report the case of a 69-year-old man with a history of severe RA successfully treated with abatacept, who showed unusually rapid progression of undifferentiated multi-metastatic carcinoma. DISCUSSION: Although no significant increase in malignancy has been reported in abatacept-treated patients, several case reports have documented the possible association with the acceleration of the progression of malignancy. Here, abatacept may have altered immune surveillance and hence allowed tumor growth.