It is not clear whether this mechanism is important in the establishment of tumor metastases in all models or that it is critical in the human disease, and indeed there is emerging evidence of the importance of other tumorderived factors such as IL, IL, and connective tissue growth factor. However, this and other evidence suggest that not only are the bone and bone marrow a conducive microenvironment or soil for metastatic breast cancer growth, but that bone undergoing high turnover or breakdown may be particularly permissive to tumor establishment and growth. Although the precise mechanism of the reduction in bone mass after AAG administration is difficult to determine, the in vitro data suggests that it may be the result of enhanced osteoclast differentiation andor survival.The increased numbers of osteoclasts in the absence of an accompanying increase in osteoblast numbers in vivo indicate that this is indeed likely to be the major cause of the lower bone mass in these mice.Moreover, because this was evident in nude mice, which already have low bone mass, it suggests that AAG has potent effects upon the osteoclast lineage and that this is not dependent on the presence or absence of lymphocytes.To date, the in vivo effects of AAG in the tumor models and the tumor nave mice have only been examined at a single dose using a single treatment schedule.Designed to observe maximal benefit of the drug, it was, therefore, surprising to see a strong enhancement of bone metastasis at a drug concentration close to the maximal tolerated dose.Further dosing and treatment schedules will be required to further Letermovir define the potential severity of the effects of AAG upon the bone microenvironment and its impact upon tumor growth.Our studies in vitro are in strong accord with our in vivo findings.The presence of tumors at sites of the skeleton other than that of the hind limbs was determined by fluorescent imaging.B, corresponding fluorescent image of the hind limb osteolytic tumor shown by fluorescent imaging.F, spine metastases were also identified in the vehicle control group as previously reported for this model; however, these were less numerous and smaller in size.G, graphical representation of the incidence of bone metastasis to various sites as determined by fluorescent imaging.A, AAG significantly enhanced osteoclast formation at and nmolL in mouse bone marrowosteoblast cocultures over a day period.Cellular toxicity was observed at higher concentrations of AAG.B, AAG significantly enhanced osteoclastogenesis in mouse bone marrow cultures in the presence of soluble RANKL and MCSF before cellular toxicity.E, AAG enhanced the size of the osteoclasts in vitro when compared with the positive control and the vehicle control.Arrows, examples of osteoclasts in vitro illustrating the size differences.F, a model of human osteoclast formation was done using human cord bloodderived progenitors cultured with soluble RANKL and MCSF.This is supported by previous findings that heat shock and oxidative stress in the premonocytic line U increases thioredoxin expression via activation of HSF. AAG is known to have profound effects upon cancer cell gene expression, increasing the expression of genes that may aid in tumor cell survival andor growth in bone.

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