Insulin-like growth factors modulate the growth inhibitory effects of XXXX on MCF-7 @entity0 cells.

@entity1 @entity172 @entity4878 @entity0 @entity5 @entity442 @entity5100 @entity53 @entity2856 @entity1968
@entity4878 are currently being tested for the treatment and prevention of several @entity1 @entity5 , including @entity0 . However, the anti- @entity5 and growth inhibitory mechanisms of @entity4878 are not well understood. @entity1968 (RA) inhibits the growth of the @entity172 receptor-positive (ER+) @entity0 cell line, MCF-7, in a reversible and dose-dependent manner. In contrast, @entity442 , @entity5100 ) and insulin are potent stimulators of the proliferation of MCF-7 and several other @entity0 cell lines. Pharmacologic doses of RA (> or = 10(-6) M) completely inhibit @entity442 -stimulated MCF-7 cell growth. Published data suggest that the growth inhibitory action of RA on IGF-stimulated cell growth is linear and dose-dependent, similar to RA inhibition of unstimulated or @entity53 -stimulated MCF-7 cell growth. Surprisingly, we have found that @entity442 or insulin-stimulated cell growth is increased to a maximum of 132% and 127%, respectively, by cotreatment with 10(-7) M RA, and that 10(-9) - 10(-7) M RA increase cell proliferation compared to @entity442 or insulin alone. MCF-7 cells that stably overexpress @entity5100 are also resistant to the growth inhibitory effects of 10(-9) - 10(-7) M RA. Treatment with the @entity442 receptor blocking antibody, alpha IR-3, restores RA-induced growth inhibition of @entity442 -treated or @entity5100 -overexpressing MCF-7 cells, indicating that the @entity2856 is mediating these effects. IGFs cannot reverse all RA effects since the altered cell culture morphology of RA-treated cells is similar in growth-inhibited cultures and in @entity5100 expressing clones that are resistant to RA-induced growth inhibition. These results indicate that RA action on MCF-7 cells is biphasic in the presence of @entity442 or insulin with 10(-9) - 10(-7) M RA enhancing cell proliferation and > or = 10(-6) M RA causing growth inhibition. As @entity442 and @entity5100 ligands are frequently detectable in @entity0 tissues, their potential for modulation of RA effects should be considered when evaluating @entity4878 for use in in vivo experimental studies and for clinical purposes. Additionally, the therapeutic use of inhibitors of IGF action in combination with RA is suggested by these studies.
