These results clearly and unequivocally demonstrate that the amifostine nanoparticles developed in our laboratory provides significant protection from acute whole-body gamma irradiation injury in mice.

We have previously reported that although SOX9 is a transcription factor, it is often localized in the cytoplasm of some invasive and metastatic breast carcinomas. To determine whether cytoplasmic compartmentalization is a common mechanism utilized by cancer cells to proliferate indefinitely, SOX9 localization was examined at different stages of development in normal mouse mammary glands and in cancer cells. We show here that SOX9 expression is nuclear in ductal epithelial cells throughout mammary gland development and differentiation but is localized in the cytoplasm of some breast cancer cell lines (BCCLs). Furthermore, cytoplasmic localization of SOX9 is associated with abrogation of the growth arrest response of breast cancer cells and results from dysregulated HDAC activity rather than defects in its nuclear export. Immuno-precipitation and immunoblot studies revealed that inhibiting HDAC activity with Trichostatin A can rescue this defect by up-regulating acetylated SOX9 and p21 expression that results in increased cell death. Our data suggests nuclear SOX9 expression parallels development and differentiation but cytoplasmic SOX9 expression is associated with abrogation of growth arrest response of breast cancer cells. Such expressions may be a common mechanism utilized by some transformed breast cancer cells to proliferate indefinitely.

No abstract

Recent evidence has demonstrated an appreciable expression of metallothionein (MT) in erythrocytes. However, the induction of the MT protein by hematopoietic growth factors and its subsequent functional significance on clonal expansion or differentiation of erythroid progenitor cells remain elusive. We therefore examined the effects of growth factors erythropoietin (EPO), granulocyte-monocyte colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3) on MT gene expression in erythroid progenitor K562 cell line. EPO, but not IL-3 or GM-CSF, induced a 3-fold increase in MT transcripts in K562 cells. MT induction was associated with EPO-induced cellular proliferation, suggesting a specific role for MT induction by EPO in erythroid progenitor cells. However, EPO- or sodium butyrate-induced differentiation as monitored by hemoglobin formation was inhibited in K562 cells stably transfected with an expression vector containing human MT-IIA gene. This inhibition of differentiation was partially reversed in these cells by an MT antisense phosphorothioate oligonucleotide. Furthermore, the MT-induced inhibition of differentiation was associated with downregulation of EPO receptor transcripts in K562 cells. These data suggest that, among growth factors required for erythropoiesis, EPO is a potent inducer of MT, and that MT may plays a significant role in EPO-induced proliferation, but not in the erythroid-specific differentiation of the progenitor cells.

These findings clearly demonstrate the feasibility of developing an effective oral formulation of WR-1065 as a radioprotective agent.