Rationale Cyclic AMP (cAMP)-protein kinase A (PKA) signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. Objective To examine whether PDE4 was involved in regulating ethanol intake. Methods The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. Results Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. Conclusions These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.
Anti-angiogenic therapy targeting the tumor vasculature has demonstrated clinical benefits in certain types of tumors. However, many patients develop resistance and eventually progress on anti-angiogenic therapy. The mechanism of resistance is largely unknown and warrants extensively investigation. We developed a human xenograft tumor model (M24met/R) in mice that has acquired resistance to VEGF receptor tyrosine kinase inhibitors (VEGFR TKI), by chronically treating the parental M24met tumors (M24met/P) with PF-0337210 (20-40 mg/kg, QD, PO) and serially passaging resistant tumor fragments in nude mice. M24met/R tumors were also resistant to axitinib, a selective VEGFR TKI in late stage clinical development. Immunohistochemical (IHC) staining revealed higher degree of hypoxia and lower microvessel density in M24met/R tumors compared to parental tumors. Compared with those in M24met/P, vessels in M24met/R tumors appeared to be larger in diameter and more mature as shown by high incidence of co-localization between endothelial cells and perivascular cells (CD31+Desmin+). Microarray analysis of tumor lysates (human UA133 2.0, mouse 430 2.0 chip) revealed distinct gene expression profiles between M24met/R tumors and size-matched M24met/P tumors. Of note, several angiogenesis-related genes, including human VEGF, bFGF, integrin α5β1, IL-8, PDGF,CSF and murine VEGF, integrin α5β1, ALK1 (activin receptor-like kinase 1), IL-8, c-Met, IL-6 were up-regulated in M24met/R tumors, whereas murine VEGFR1 and 2, PROX1, PDGFR and endogenous angiogenic inhibitor TSP-1 were down-regulated in the resistant tumors. The above observations were verified with ELISA and/or IHC. Next, targeted combination approaches were applied in an attempt to circumvent M24met/R resistance to axitinib. Concurrent administration of axitinib plus either anti-IL-8 monoclonal antibody (mAb), c-Met inhibitor, anti-integrin α5 mAb or anti-ALK1 mAb significantly improved anti-tumor efficacy compared to single agents alone. IHC analyses showed that combinatorial therapy of anti-ALK1 plus axitinib reduced the amount of CD31+Desmin+ vessels compared to axitinib alone, suggesting that targeting ALK1 destroyed VEGFR TKI-resistant vessels. Together, our results suggested that multiple alternative angiogenic factors contributed to the acquired resistance of M24met/R melanoma to VEGFR TKI. Combination treatment using inhibitor of IL-8, c-Met, integrin α5β1 or ALK1 with VEGFR TKI may represent a new strategy to mitigate resistance to VEGFR TKI in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3270. doi:10.1158/1538-7445.AM2011-3270
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