Monday, July 27, 2009
Revisiting Old Drugs as Novel Agents for Retinoblastoma
A new study led by researchers at Memorial Sloan Kettering Cancer Center discovered the anticancer activity of an already-approved class of drugs and suggests that administering them in a novel way may be effective in the treatment of retinoblastoma — the most common type of eye tumor in children. The study is published in the July issue of Investigative Ophthalmology and Visual Science.
Using high-throughput drug-screening technology, researchers identified the potent cancer-fighting ability of cardenolides, which are prescribed to treat various heart conditions including heart failure, but have been reported to cause high toxicity in patients. The work reports on the efficacy of this novel class of agents in mouse models bearing retinoblastoma and proposes the use of intra-arterial infusion of these drugs as a way to attack the disease and lessen side effects.
Intra-arterial administration is a method that allows local delivery of high doses of chemotherapy agents through a tiny catheter inserted directly into the optic artery while bypassing the patient’s general blood circulation, thus reducing systemic side effects.
“This new technique has allowed us to revisit approved agents that had previously been neglected due to their intolerable side effects,” said study co-author David Abramson, MD, Chief of the Ophthalmic Oncology Service at Memorial Sloan Kettering. “Based on our findings, we would encourage the study of intra-arterial infusion of cardenolides in patients with retinoblastoma.”
The study was conducted at the High-Throughput Screening (HTS) Core Facility at Memorial Sloan Kettering, which screens a chemical library of 350,000 potential anticancer compounds against cancer cells from human tissue samples in an effort to discover novel drug candidates. The study’s researchers used HTS to test 2,640 approved drugs for activity in human retinoblastoma cell lines and identified cardenolides as a new class of antitumor agents.
“Our findings provide insight into the mechanism of action of cardenolides in retinoblastoma cells,” said the study’s senior author, Hakim Djaballah, PhD, Director of the HTS Core Facility at Memorial Sloan Kettering.
Subsequent testing in mice showed the therapeutic effect of these drugs against the disease. “When tested in a mouse model of retinoblastoma, the cardenolides induced complete tumor regression in the treated mice,” said Dr. Abramson, who has obtained FDA approval to administer these drugs to retinoblastoma patients on a compassionate-use basis. This is the first FDA approval based on work conducted at Memorial Sloan Kettering’s HTS Core Facility.
“Our collaboration — which began in 2005 thanks to a chance meeting and a new appreciation of each other’s research interests — is a successful example of performing drug discovery in an academic setting and utilizing our vastly different disciplines to benefit a disease that is not a high priority for pharmaceutical or biotech companies,” said Dr. Djaballah of his work with Dr. Abramson.