Phase I trial of ATRA-IV and depakote in patients with advanced solid tumor malignancies

Kevin A. David, Nigel P. Mongan, Christopher Smith, Lorraine J. Gudas, David M. Nanus

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Retinoic acid derivatives have shown their greatest benefit in acute promyelocytic leukemia, but have also demonstrated pre-clinical anti-cancer effects in some solid tumors. Histone deacetylase inhibitors, by upregulating gene expression, are able to limit cancer cell proliferation and induce apoptosis. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid has been previously studied in hematologic malignancies. We conducted a phase I two-step dose escalation trial of the liposomal ATRA analog ATRA-IV and divalproex sodium (Depakote®) in nine patients with advanced solid tumors refractory to prior therapy. Side effects attributed to therapy had a severity ≤grade 2 and included skin toxicity and thrombocytopenia. The best disease response seen was disease stabilization in one patient. Expression of cellular retinoic acid binding protein-2 in peripheral blood mononuclear cells was detected as a marker of drug effect. The maximum tolerated dose (MTD) of both drugs in combination could not be established due to early closure of the trial resulting from a halt in the commercial availability of ATRA-IV.

Original languageEnglish (US)
Pages (from-to)678-684
Number of pages7
JournalCancer Biology and Therapy
Volume9
Issue number9
DOIs
StatePublished - May 1 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology

Keywords

  • ATRA
  • Cancer
  • Histone deacetylase inhibitors
  • Phase I trial
  • Valproic acid

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