Enhancement of Tamoxifen-Induced Suppression of Insulin-Like Growth Factor I Gene Expression and Serum Level by a Somatostatin Analogue

Abstract

Mitogenic responsivity of many neoplasms to IGF-I has been detected in a variety of in vivo and in vitro experimental systems. This has led to the proposal that pharmacological reduction of IGF-I bioactivity might represent a novel non-cytotoxic palliative therapy. We recently reported that tamofixen, a commonly used antiestrogen antineoplastic agent, significantly suppresses IGF-I gene expression and serum IGF-I levels. We report here that the somatostatin analogue octreotide, previously demonstrated to reduce acromegalic levels of IGF-I towards normal, decreased serum IGF-I to 70 ± 4% (mean ± SD) of control values and hepatic IGF-I expression to 65 ± 10% of control values in a short-term non-acromegalic rat model. Tamoxifen reduced serum IGF-I to 74 ± 12 % of control values and hepatic IGF-I expression to 46 ± 9% of control values in this model, but the combination of octreotide and tamoxifen reduced serum IGF-I concentration to 49 ± 10% of control values and hepatic IGF-I gene expression to 12 ± 9% of control values. The levels of serum IGF-I and hepatic IGF-I gene expression were significantly less in animals treated with the combination of octreotide and tamoxifen than in animals treated with either agent alone (p <.01). This combination represents a novel pharmacological strategy for suppressing IGF-I gene expression that may be relevant to the design of clinical trials.