This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schrump, D. S. Articles by Steinberg, S. M. Search for Related Content PubMed PubMed Citation Articles by Schrump, D. S. Articles by Steinberg, S. M.

Clinical and Molecular Responses in Lung Cancer Patients Receiving Romidepsin

Authors' Affiliations:¹ Thoracic Oncology Section Surgery Branch, ² Medical Oncology Branch, ³ Biostatistics and Data Management Section, Center for Cancer Research and ⁴ Cancer Therapy Evaluation Program, National Cancer Institute; ⁵ Clinical Cardiology Section, National Heart-Lung-Blood Institute, NIH, Bethesda, Maryland and ⁶ Functional Genomics Facility, University of Chicago, Chicago, Illinois

Requests for reprints: David S. Schrump, Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 4-3942, 10 Center Drive, MSC 1201, Bethesda, MD 20892. Phone: 301-496-2127; Fax: 301-451-6934; E-mail: david_schrump{at}nih.gov.

Purpose: Our preclinical experiments indicated that Romidepsin (Depsipeptide FK228; DP) mediates growth arrest and apoptosis in cultured lung cancer cells. A phase II trial was done to examine clinical and molecular responses mediated by this histone deacetylase inhibitor in lung cancer patients.

Experimental Design: Nineteen patients with neoplasms refractory to standard therapy received 4-h DP infusions (17.8 mg/m²) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of two identical 21-day cycles. Plasma DP levels were evaluated by liquid chromatography–mass spectrometry techniques. A variety of molecular end points were assessed in tumor biopsies via immunohistochemistry techniques. Long oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after DP exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections.

Results: Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in one individual. No significant cardiac toxicities were observed. Maximum steady-state plasma DP concentrations ranged from 384 to 1,114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in nine patients. DP enhanced acetylation of histone H4, increased p21 expression in lung cancer cells, and seemed to shift global gene expression profiles in these cells toward those detected in normal bronchial epithelia.

Conclusion: Although exhibiting minimal clinical efficacy at this dose and schedule, DP mediates biological effects that may warrant further evaluation of this histone deacetylase inhibitor in combination with novel-targeted agents in lung cancer patients.