Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts

Eiseman, Julie L.; Lan, Jing; Lagattuta, Theodore F.; Hamburger, Deborah R.; Joseph, Erin; Covey, Joseph M.; Egorin, Merrill J.

doi:10.1007/s00280-004-0865-3

Cited by 138 publications

(111 citation statements)

References 46 publications

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“…Blockade of the ATPase activity of Hsp90 have effectively inhibited cell signaling molecules in proliferating cancer cells (43). However, geldanamycin and its derivatives have some significant limited pharmaceutical properties as well as toxicities in clinical trials (14,44). For these reasons, the development of novel Hsp90 inhibitors has been an area of intense research.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Song

Chaerkady

Tan

et al. 2008

Molecular Cancer Therapeutics

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Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose-and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

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Section: Discussionmentioning

confidence: 99%

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Song

Chaerkady

Tan

et al. 2008

Molecular Cancer Therapeutics

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“…53 Others have reported HSPs expressed in glomeruli and tubules of some SLE patients. 9 However, our assessment of HSP90 expression in our control and HSP90-inhibited groups as well as C57BL/6 mouse kidneys showed that the diseased mice exhibited elevated HSP90 in tubules but not in glomeruli.…”

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

“…We selected 17-DMAG over GA as our in vivo inhibitor based on published results showing reduced hepatotoxicity in vivo when compared to GA or 17-allylamino-17-demethoxygeldanamycin (17-AAG). 16,18,53,54 Dosages were selected based on studies showing effective treatment and minimal toxicity at dosages under 15 mg/kg administered 3 days per week for 3 weeks. 55 We injected MRL/lpr mice with 17-DMAG 3 days a week on alternating days for 6 weeks, (a) Linear regression of grouped proteinuria scores showed control mice exhibited increased proteinuria, while mice treated with 17-DMAG did not increase in proteinuria.…”

Section: Hsp90 Inhibition Reduced Inflammatory Mediator Production Inmentioning

confidence: 99%

“…Inhibition of HSP90 by 17-DMAG has been shown to affect HSP90 and HSP70 expression both in vivo and clinically. 53,54 In addition, we questioned if HSP90 expression is altered in MRL/lpr mice compared to other mice strains such as the C57BL/6 strain. To answer these questions, we stained frozen kidney sections with DyLight 488-conjugated anti-HSP90 or anti-HSP70 antibodies and with DAPI nuclear stain.…”

Section: Hsp90 Inhibition Reduced Inflammatory Mediator Production Inmentioning

confidence: 99%

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Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

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Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

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“…Thus, direct inhibition of HSP90 may have a much more profound effect on arsenite sensitivity and centrosome regulation than preventing induction of HSP70i. A375, HeLa and TR9-7 (p53 (-) ) cells were plated in 96 well dishes and treated for up to 3 days with 0-300 nM 17-DMAG (a potent inhibitor of HSP90 ATPase activity, (Eiseman et al, 2005)) combined with either 0, 0.5, 1, 2.5 or 5 μM arsenite. Viability was measured using AlamarBlue after 48 h of treatment ( Figure 6).…”

Section: Disruption Of Hsp70/hsp90 Activity Enhances Effectiveness Ofmentioning

confidence: 99%

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Taylor

McNeely

Miller

et al. 2008

Toxicology and Applied Pharmacology

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Arsenite, a known mitotic disruptor, causes cell cycle arrest and cell death at anaphase. The mechanism causing mitotic arrest is highly disputed. We compared arsenite to the spindle poisons nocodazole and paclitaxel. Immunofluorescence analysis of α-tubulin in interphase cells demonstrated that, while nocodazole and paclitaxel disrupt microtubule polymerization through destabilization and hyperpolymerization, respectively, microtubules in arsenite-treated cells remain comparable to untreated cells even at supra-therapeutic concentrations. Immunofluorescence analysis of α-tubulin in mitotic cells showed spindle formation in arsenite-and paclitaxel-treated cells but not in nocodazole-treated cells. Spindle formation in arsenite-treated cells appeared irregular and multi-polar. γ-tubulin staining showed that cells treated with nocodazole and therapeutic concentrations of paclitaxel contained two centrosomes. In contrast, most arsenite-treated mitotic cells contained more than two centrosomes, similar to centrosome abnormalities induced by heat shock. Of the three drugs tested, only arsenite treatment increased expression of the inducible isoform of heat shock protein 70 (HSP70i). HSP70 and HSP90 proteins are intimately involved in centrosome regulation and mitotic spindle formation. HSP90 inhibitor 17-DMAG sensitized cells to arsenite treatment and increased arsenite-induced centrosome abnormalities. Combined treatment of 17-DMAG and arsenite resulted in a supra-additive effect on viability, mitotic arrest, and centrosome abnormalities. Thus, arsenite-induced abnormal centrosome amplification and subsequent mitotic arrest is independent of effects on tubulin polymerization and may be due to specific stresses that are protected against by HSP90 and HSP70.

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Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts

Cited by 138 publications

References 46 publications

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

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