Salatino Mariana, Schillaci Roxana, Proietti Cecilia J, Carnevale Romina, Charreau Eduardo H, Elizalde Patricia V
Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.
Medicina (B Aires). 2004;64(2):129-34.
We addressed the effect of targeting type I insulin-like growth factor receptor (IGF-IR), with antisense strategies in in vivo growth of breast cancer cells. We used C4HD tumors from an experimental model of hormonal carcinogenesis in which medroxyprogesterone acetate induced mammary adenocarcinomas in Balb/c mice. Intratumor or systemic administration of phosphorothiolated antisense oligodeoxynucleotides (AS[S]ODN) to IGF-IR mRNA resulted in a significant inhibition of C4HD tumor growth. The antitumor effect was specific since inhibition of tumor growth was dose-dependent and no effect was observed in mice treated with sense S[S]ODN. Tumors from AS[S]ODN-treated mice showed a decrease in IGF-IR expression and in insulin receptor substrate-1 tyrosine phosphorylation. Activation of PI-3K/Akt, p42/p44 MAPK and ErbB-2 was abolished in tumors treated with AS[S]ODN. Progesterone receptor expression or activity remained invariable. This is the first demonstration that breast cancer growth can be inhibited by direct in vivo administration of IGF-IR AS[S]ODN.
我们采用反义策略，研究了靶向I型胰岛素样生长因子受体（IGF-IR）对乳腺癌细胞体内生长的影响。我们使用了激素致癌实验模型中的C4HD肿瘤，该模型中醋酸甲羟孕酮可诱导Balb/c小鼠发生乳腺腺癌。向IGF-IR mRNA瘤内或全身注射硫代磷酸化反义寡脱氧核苷酸（AS[S]ODN）可显著抑制C4HD肿瘤生长。这种抗肿瘤作用具有特异性，因为肿瘤生长的抑制呈剂量依赖性，而用正义S[S]ODN处理的小鼠未观察到任何作用。经AS[S]ODN处理的小鼠肿瘤显示IGF-IR表达及胰岛素受体底物-1酪氨酸磷酸化水平降低。在经AS[S]ODN处理的肿瘤中，PI-3K/Akt、p42/p44 MAPK和ErbB-2的激活被消除。孕酮受体的表达或活性保持不变。这是首次证明通过直接体内注射IGF-IR AS[S]ODN可抑制乳腺癌生长。
