RESUMO
In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Carcinoma Basocelular/prevenção & controle , Predisposição Genética para Doença , Pirazóis/uso terapêutico , Receptores de Superfície Celular/genética , Neoplasias Cutâneas/prevenção & controle , Sulfonamidas/uso terapêutico , Animais , Síndrome do Nevo Basocelular/complicações , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/genética , Carcinoma Basocelular/genética , Celecoxib , Quimioprevenção , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Método Duplo-Cego , Heterozigoto , Humanos , Camundongos , Camundongos Mutantes , Receptores Patched , Receptor Patched-1 , Neoplasias Cutâneas/genéticaRESUMO
There have been few reports of successful long-term culture of cells established from cutaneous basal cell carcinoma (BCC) tumors. Here, we describe techniques that have enabled us to establish three long-term cultures of BCC cells isolated from BCC tumors that arose in irradiated Patched 1 (Ptch1)(+/-) mice. All three cell lines showed cellular morphology similar to that of BCC tumors and could be propagated for at least 20 passages. In addition, similar to BCC tumors, all cell lines had lost the wildtype Ptch1 allele, expressed BCC molecular markers, and responded similarly to cyclopamine, a small molecule inhibitor of Hedgehog signaling. Finally, we describe an efficient electroporation technique for DNA transfection into the BCC cell lines and show that they have activated Hedgehog signaling activity, albeit at a level lower than that of murine BCCs in vivo. These data indicate that the cell lines are bona fide long-term cultures of BCC cells and that DNA plasmids can be introduced into the BCC cell lines with relatively high transfection efficiency using a modified electroporation technique.
