Electron micrograph of Chromobacterium violaceum, the source of depsipeptide. Courtesy of Instituto Ciência Hoje. Márcia Attias (photographer), Universidade Federal Rio de Janeiro. 2001.

Dr. Susan Bates. Courtesy of NCI. 2000.

Depsipeptide (NSC 630176)

1990 Depsipeptide (NSC 630176) is a member of the bicyclic peptide class of histone deacetylase (HDAC) inhibitors and was first isolated as a fermentation product from Chromobacterium violaceum by the Fujisawa Pharmaceutical Company. Because of its unique structure and intriguing pattern of activity in the NCI human tumor cell line screen, DTP selected it as a compound of interest in 1990.

HDAC inhibitors modulate the expression of genes by increasing histone acetylation and thereby regulating chromatin structure and transcription. They also induce terminal cell differentiation and apoptosis in cancer cells.¹

1991 In 1991, DTP began Decision Network (DN) level IIA small animal testing on depsipeptide. In vivo studies of depsipeptide showed complete remissions in three out of 10 animals in LOX melanoma using 1.44 mg/kg/day for five days (i.v.). Delayed tumor growth was observed against UACC-62 (melanoma), NCI-H522 (non-small cell lung), and MX-1 (breast) human tumor xenografts on a q4D × 3 i.v. schedule using a dose of 5.3 mg/kg/dose.

Initial development of this drug was halted due to significant cardiac toxicity in animal models. Subsequent studies performed at NCI demonstrated that administration without cardiotoxicity was possible by changing the schedule of administration from a bolus injection to a four-hour infusion.

1996 In a phase I trial involving cutaneous T-cell lymphoma and peripheral T-cell lymphoma patients, clinicians observed three partial responses and one complete response. Hyperacetylation of histone was measurable in T cells isolated from patients.

Phase II clinical trials of depsipeptide for use against T-cell lymphomas, thyroid cancer, refractory solid tumors, and other advanced cancers are ongoing at NIH's Clinical Center and at other cancer centers.²

¹ Richon VM, O'Brien JP. Histone deacetylase inhibitors: a new class of potential therapeutics agents for cancer treatment. Clin Cancer Res 2002;8:662–664.

² ClinicalTrials.gov.

Links:

A review of depsipeptide and other histone deacetylase inhibitors in clinical trials.

DTP depsipeptide poster (pdf)

“While many chemotherapy drugs work by causing damage to cells, HDAC inhibitors turn on genes in cancer cells that inhibit cell growth and eventually cause cancer cells to die.”

—Dr. Susan Bates, NCI