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Bombesin and epidermal growth factor potentiate the effect of cytotoxic LH-RH analog AN-152 in vitro.

The conjugation of doxorubicin with [D-Lys6] Luteinizing Hormone-Releasing Hormone (LH-RH), yields AN-152, a cytotoxic analog that can be targeted to tumor cells expressing LH-RH receptors. This conjugate is more potent against LH-RH receptor positive cancer cells and has less peripheral toxicity than free doxorubicin. The proliferation of MCF-7 human breast cancer cells in vitro is inhibited by AN-152 and this effect can be augmented by the up-regulation of LH-RH receptor expression through stimulation of tyrosine phosphorylation with epidermal growth factor (EGF). Bombesin and gastrin releasing peptide increase tyrosine phosphorylation and can act synergistically with EGF, as well as independently. The aim of this study was to demonstrate that bombesin enhances cytotoxic sensitivity of MCF-7 cells to AN-152 and that a significantly higher efficacy of the drug can be achieved in cells exposed to both bombesin and EGF. The cells were pretreated with bombesin and/or EGF, and then exposed to 0-10 micro M AN-152 for 96 h for determination of cytotoxicity. In addition, cells pretreated with bombesin and/or EGF were exposed for 1 h to 0.6 micro M AN-152 labeled with a two-photon fluorophore (AN-152:C625) for fluorescent imaging of drug entry. Bombesin as well as EGF increased the uptake and cytotoxicity of AN-152 in MCF-7 cells. The exposure of the cells to both EGF and bombesin produces a synergistic effect and results in increased cellular entry and cytotoxicity of AN-152. These results suggest that the activation of LH-RH receptors by compounds that increase tyrosine phosphorylation could further improve the response to targeted chemotherapy with AN-152.