Activation of protein kinase CB (PKCB) has been repeatedly implicated in tumor-induced angiogenesis. The PKCB-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKCB has now also been implicated in tumor cell proliferation, apoptosis, and tumor invasiveness. Herein, we show that Enzastaurin has a direct effect on human tumor cells, inducing apoptosis and suppressing the proliferation of cultured tumor cells. Enzastaurin treatment also suppresses the phosphorylation of GSK3B ser9 , ribosomal protein S6 S240/244 , and AKT Thr308 . Oral dosing with Enzastaurin to yield plasma concentrations similar to those achieved in clinical trials significantly suppresses the growth of human glioblastoma and colon carcinoma xenografts. As in cultured tumor cells, Enzastaurin treatment suppresses the phosphorylation of GSK3B in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3B phosphorylation to a similar extent in peripheral blood mononuclear cells (PBMCs) from these treated mice. These data show that Enzastaurin has a direct antitumor effect and that Enzastaurin treatment suppresses GSK3B phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3B phosphorylation may serve as a reliable pharmacodynamic marker for Enzastaurin activity. With previously published reports, these data support the notion that Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis.
Informal/family caregivers are a fundamental source of care for cancer patients in the United States, yet the population of caregivers, their tasks, psychosocial needs and health outcomes are not well understood. Changes in the nature of cancer care and its delivery, along with the growing population of survivors and by consequence, their caregivers, warrant increased attention to the roles and demands of caregiving. This paper reviews current evidence presented in a two-day meeting to examine the state of the science of informal cancer caregiving convened by the National Cancer Institute and National Institute for Nursing Research. The meeting sought to define who is an informal cancer caregiver, summarize the state of the science in informal cancer caregiving, and describe both the kinds of interventions developed to address caregiving challenges and the various outcomes used to evaluate their impact. This paper offers recommendations for moving science forward in four areas: (1) improve estimation of the prevalence and burden of informal cancer caregiving; (2) advance development of interventions designed to improve outcomes in cancer patients, caregivers, and patient-caregiver dyads; (3) generate and test strategies to integrate caregivers into formal healthcare settings; and (4) promote use of technology to support informal cancer caregivers.
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