ArticleClinical cancer research : an official journal of the American Association for Cancer Research2008
A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 59 citations in OpenAlex.
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- HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review).Oncology reports · 2023Review
- Chaperone-assisted E3 ligase CHIP: A double agent in cancer.Genes & diseases · 2022Review
- Traditional and Novel Mechanisms of Heat Shock Protein 90 (HSP90) Inhibition in Cancer Chemotherapy Including HSP90 Cleavage.Biomolecules & therapeutics · 2019Article
- HSP90 inhibitor 17-DMAG effectively alleviated the progress of thoracic aortic dissection by suppressing smooth muscle cell phenotypic switch.American journal of translational research · 2019Article
- The HSP90 inhibitor NVP-AUY922 inhibits growth of HER2 positive and trastuzumab-resistant breast cancer cells.Investigational new drugs · 2018Article
- Inhibition of heat shock protein 90 improves pulmonary arteriole remodeling in pulmonary arterial hypertension.Oncotarget · 2016Article
- Phase I study of tanespimycin in combination with bortezomib in patients with advanced solid malignancies.Investigational new drugs · 2013Article
- Molecular targets and mechanisms of radiosensitization using DNA damage response pathways.Future oncology (London, England) · 2013Review
- Identification, design and bio-evaluation of novel Hsp90 inhibitors by ligand-based virtual screening.PloS one · 2013Article
- Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers.Biochimica et biophysica acta · 2012Review
- Monitoring the induction of heat shock factor 1/heat shock protein 70 expression following 17-allylamino-demethoxygeldanamycin treatment by positron emission tomography and optical reporter gene imaging.Molecular imaging · 2012Article
- Multi-drug delivery to tumor cells via micellar nanocarriers.International journal of pharmaceutics · 2011Article
- Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors.Investigational new drugs · 2011Article
- Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease.British journal of cancer · 2011Article
- Targeting the dynamic HSP90 complex in cancer.Nature reviews. Cancer · 2010Review
- Safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of sorafenib and tanespimycin.Clinical cancer research : an official journal of the American Association for Cancer Research · 2010Article
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Authors and funding
19 authors at 4 institutions in 2 countries.
Funding
Abstract
purposeBoth heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors. EXPERIMENTAL
designDuring the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity.
resultsTwenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m(2) irinotecan and 375 mg/m(2) 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G(2)-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD.
conclusionsThe combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m(2) irinotecan and 300 mg/m(2) 17AAG.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.