ArticleClinical cancer research : an official journal of the American Association for Cancer Research2010
Phase I pharmacokinetic and pharmacodynamic evaluation of combined valproic acid/doxorubicin treatment in dogs with spontaneous cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 35 citations in OpenAlex.
- Comparative Cancer Genetics and Veterinary Therapeutics in Dogs and Cats: A Species-Aware Framework for Comparative Oncology.Life (Basel, Switzerland) · 2026Review
- HDACi induces apoptosis of osteosarcoma cells by inhibiting the MAPK pathway.Scientific reports · 2026Article
- Building a Therapeutic Bridge Between Dogs and Humans: A Review of Potential Cross-Species Osteosarcoma Biomarkers.International journal of molecular sciences · 2025Review
- Comparative epigenomics to clinical trials in human breast cancer and canine mammary tumor.Animal cells and systems · 2025Review
- Preclinical and clinical progress for HDAC as a putative target for epigenetic remodeling and functionality of immune cells.International journal of biological sciences · 2021Review
- Epigenetic Mechanisms in Canine Cancer.Frontiers in oncology · 2020Review
- Article
- The histone deacetylase inhibitor panobinostat is a potent antitumor agent in canine diffuse large B-cell lymphoma.Oncotarget · 2018Article
- Validation of epigenetic mechanisms regulating gene expression in canine B-cell lymphoma: An in vitro and in vivo approach.PloS one · 2018Article
- Article
- Pulsed Electromagnetic Field Stimulation Promotes Anti-cell Proliferative Activity in Doxorubicin-treated Mouse Osteosarcoma Cells.In vivo (Athens, Greece) · 2017Article
- Defining the Value of a Comparative Approach to Cancer Drug Development.Clinical cancer research : an official journal of the American Association for Cancer Research · 2016Review
- Article
- Epigenetic alterations in osteosarcoma: promising targets.Molecular biology reports · 2014Review
- Simultaneous determination of asenapine and valproic acid in human plasma using LC-MS/MS: Application of the method to support pharmacokinetic study.Journal of pharmaceutical analysis · 2013Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
purposeHistone deacetylase inhibitors (HDACi) are targeted anticancer agents with a well-documented ability to act synergistically with cytotoxic agents. We recently showed that the HDACi valproic acid sensitizes osteosarcoma cells to doxorubicin in vitro and in vivo. As there are no published reports on the clinical utility of HDACi in dogs with spontaneous cancers, we sought to determine a safe and biologically effective dose of valproic acid administered prior to a standard dose of doxorubicin.
methodsTwenty-one dogs were enrolled into eight cohorts in an accelerated dose-escalation trial consisting of pretreatment with oral valproic acid followed by doxorubicin on a three-week cycle. Blood and tumor tissue were collected for determination of serum valproic acid concentration and evaluation of pharmacodynamic effects by immunofluorescence cytochemistry and immunohistochemistry. Serum and complete blood counts were obtained for determination of changes in doxorubicin pharmacokinetics or hematologic effects.
resultsAll doses of valproic acid were well tolerated. Serum valproic acid concentrations increased linearly with dose. Doxorubicin pharmacokinetics were comparable with those in dogs receiving doxorubicin alone. A positive correlation was detected between valproic acid dose and histone hyperacetylation in peripheral blood mononuclear cells. No potentiation of doxorubicin-induced myelosuppression was observed. Histone hyperacetylation was documented in tumor and peripheral blood mononuclear cells. Responses included 2 of 21 complete, 3 of 21 partial, 5 of 21 stable disease, and 11 of 21 progressive disease.
conclusionsValproic acid can be administered to dogs at doses up to 240 mg/kg/day prior to a standard dose of doxorubicin. In addition, we have developed the pharmacokinetic/pharmacodynamic tools necessary for future studies of novel HDACi in the clinical setting of canine cancer.
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