Bruce A. Chabner

Interview with Dr. Ryan Corcoran on the potential clinical applications of cell-free DNA analysis in patients with cancer. (10:36)Download The capacity to detect new cancers, treatment-resistant variants, and tumor heterogeneity by noninvasive technology on the basis of tumor DNA in the blood promises to revolutionize cancer detection, prevention, and treatment.

PURPOSE: Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors. METHODS: In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy. RESULTS: HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials. CONCLUSION: HDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

METHOTREXATE, the most widely used antimetabolite in cancer chemotherapy, has an essential role in the treatment of such diverse diseases as acute lymphocytic leukemia, non-Hodgkin's lymphoma, osteosarcoma, choriocarcinoma, head and neck cancer, and breast cancer.1 It has also become an important therapeutic alternative in the treatment of severe psoriasis2 and in the suppression of graft-versus-host disease after bone-marrow transplantation,3 as well as in the experimental treatment of various rheumatic diseases after primary therapy has failed.4 Through pharmacologic research we have gained an understanding of the basic steps in the action of methotrexate, including its transport across cell membranes, its intracellular . . .