ABSTRACT
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.
Evaluamos el efecto del bloqueo de la expresión del receptor del factor de crecimiento semejante a lainsulina tipo I (IGF-IR) sobre el crecimiento in vivo de cáncer de mama empleando una estrategiaantisentido. Utilizamos el adenocarcinoma mamario murino progestágeno-dependiente C4HD. La administración intratumoral o sistémica de oligodeoxinucleótidos antisentido fosfotiolados al ARNm del IGF-IR (AS[S]ODN) inhibió el crecimiento tumoral. El efecto antitumoral fue específico debido a su dosis-dependencia y a la faltade efecto en ratones tratados con el S[S]ODN sentido. Los tumores obtenidos de ratones tratados con AS[S]ODN mostraron: disminución en la expresión de IGF-IR y en la fosforilación del sustrato del receptor de insulina-1, inhibición de la activación de PI-3K/Akt, p42/p44MAPK y ErbB-2, mientras que la expresión y activación del receptor de progesterona no se afectó. Es la primera demostración que el
Subject(s)
Animals , Female , Mice , Adenocarcinoma/metabolism , Mammary Neoplasms, Experimental/metabolism , Oligodeoxyribonucleotides, Antisense , Receptor, IGF Type 1/antagonists & inhibitors , Receptors, Somatomedin/metabolism , Animal Diseases , Adenocarcinoma/drug therapy , Dose-Response Relationship, Drug , Medroxyprogesterone , Mice, Inbred BALB C , Mammary Neoplasms, Experimental/drug therapy , Oligodeoxyribonucleotides, Antisense , RNA, Messenger/drug effects , Receptor, IGF Type 1/drug effects , Receptor, IGF Type 1/metabolism , Tumor Cells, CulturedABSTRACT
The effect [quot ]in vivo[quot ] of 11 beta-hydroxy-pregna-1,4-diene-3,20-dione (delta HOP) in acute and chronic treatment was studied in mice compared to those treated with dexamethasone and vehicle. In acute experiments an injection of 2 mg/100 g body weight of delta HOP had a maximal inhibitory effect in 3H-uridine incorporation by thymocytes 18 h after the injection, disappearing 36 h later, meanwhile no change was observed in plasma corticosterone levels at any time. The dose 0.033 mg/100 g body weight of dexamethasone produced a high inhibition 5 h after the injection, and a significant decrease in plasma corticosterone was produced at this time; the effect disappeared at 24 h. In the chronic treatment delta HOP produced the maximal inhibition 5 h after the treatment; this effect was maintained until 36 h and disappeared at 48 h without change in corticosterone levels. Meanwhile dexamethasone produced the same inhibition as delta HOP 5 h after the treatment; this effect disappeared after 18 h. In those animals plasma corticosterone decreased during longer time than in acute treatment, since it continued lower than normal at 18 h and it recovered at 24 h. After 5 h of a chronic treatment delta HOP did not change thymus and spleen weights, but they decreased with dexamethasone treatment. These results suggest that the [quot ]in vivo[quot ] actions of delta HOP is different from that of glucocorticoids.