Andrea K McCollum

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17-Allylamino-demethoxygeldanamycin (17-AAG), currently in phase I and II clinical trials as an anticancer agent, binds to the ATP pocket of heat shock protein (Hsp90). This binding induces a cellular stress response that up-regulates many proteins including Hsp27, a member of the small heat shock protein family that has cytoprotective roles, including(More)
PURPOSE To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins. EXPERIMENTAL DESIGN A phase I dose escalating trial in patients with(More)
PURPOSE To evaluate the effects of combining the multiple receptor tyrosine kinase inhibitor AEE788 and histone deacetylase (HDAC) inhibitors on cytotoxicity in a broad spectrum of cancer cell lines, including cisplatin-resistant ovarian adenocarcinoma cells. EXPERIMENTAL DESIGN Multiple cancer cell lines were treated in vitro using AEE788 and HDAC(More)
Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) and its derivative 17-allylamino-demethoxygeldanamycin (17-AAG), recent reports indicate that these inhibitors lack significant single-agent clinical activity. Resistance to Hsp90 inhibitors has been previously linked to expression of P-glycoprotein (P-gp) and(More)
Benzoquinone ansamycin antibiotics such as geldanamycin (GA) bind to the NH(2)-terminal ATP-binding domain of heat shock protein (Hsp) 90 and inhibit its chaperone functions. Despite in vitro and in vivo studies indicating promising antitumor activity, derivatives of GA, including 17-allylaminogeldanamycin (17-AAG), have shown little clinical efficacy as(More)
3030 Background: Therapy directed at the molecular chaperone HSP90 causes degradation of multiple client proteins critical in cancer cell proliferation and survival. 17AAG, a HSP90 directed agent, has demonstrated in vitro and in vivo antitumor effects in a variety of cancers. METHODS We performed a phase I trial to determine the maximum tolerated dose(More)
3058 Background: 17-AAG, a benzoquinone ansamycin derivative that targets the heat shock protein hsp90, is currently undergoing clinical evaluation in phase I/II trials. We have demonstrated sequence dependent synergy with Gem and CDDP in combination with 17-AAG in vitro. METHODS A phase I trial was conducted in patients with solids tumors receiving the(More)
Bag3 is a Bag family co-chaperone that regulates the ATPase activity of Hsp70 (heat-shock protein 70) chaperones. Recent studies have demonstrated that Bag3 can initiate macroautophagy in co-operation with small heat-shock protein HspB8. In this issue of the Biochemical Journal, Fuchs and co-workers have discovered the IPV motif in Bag3 that is necessary(More)
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