Drug Slows Prostate Tumor Growth By Keeping Vitamin A Active

Daily injections of the agent VN/14-1 resulted in up to a 50 percent decrease in tumor volume in mice implanted with human prostate cancer cells, reported Aakanksha Khandelwal, Ph.D., November 6, 2007 at the American Association for Cancer Research Centennial Conference on Translational Cancer Medicine. No further tumor growth was seen during the five-week study, Khandelwal reports.

Importantly, VN/14-1 exerted its effects in multiple ways, which is the hallmark of a so-called promiscuous drug, according to the study's senior investigator, Vincent C.O. Njar, Ph.D., associate professor in the Department of Pharmacology and Experimental Therapeutics within UMB's School of Medicine.

"This potent agent causes cancer cells to differentiate, forcing them to turn back to a non-cancerous state -- which is what we expected it would do -- but it also stops cancer growth by arresting the cell cycle and pushes cells to die by inducing programmed cell death," Njar said.

"These functions were unexpected and wonderfully surprising," he said. "I am not aware that any other drug currently used to treat prostate cancer targets so many pathways."

Vitamin A, when converted by the body into retinoic acid, is known to be involved in maintaining the normal growth of cells, and other research has shown that prostate cancer cells contain five to eight times less retinoic acid than normal prostate cells. Njar's laboratory developed a number of compounds, including VN/14-1, with the aim of inhibiting the normal breakdown of retinoic acid in cancer cells.

The agent is similar in function to the well-known acne and anti-aging therapy, Retin-A, as well as to the leukemia drug Vesanoid. These products, known as retinoids, add all-trans retinoic acid (ATRA) to skin or cancer cells. VN/14-1, which is a retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of ATRA, keeping more retinoic acid available within cancer cells so that the chemical can redirect these cells back into their normal growth patterns, which includes programmed cell death.

"Our idea is that rather than give extra ATRA, we would prevent ATRA already available within cells from being broken down," Njar said. "We now call VN/14-1 an atypical RAMBA because in addition to blocking ATRA metabolism, it has other multiple desirable anti-cancer effects."

VN/14-1 works by blocking the CYP26 enzyme that actually transforms ATRA into inactive compounds, he says. The researchers have successfully tested VN/14-1 in breast cancer cells and have been funded to study the compound in preclinical studies that can lead to a Phase I human clinical trial.

In this study, the researchers found in mouse models of human prostate cancer that a 5 mg/kg (milligram per kilogram) dose injected daily resulted in a 33 percent reduction in tumor size; a dose twice as large reduced tumors by 50 percent.

They also tested a dose of 20 mg/kg through oral and intravenous administration to study the concentration of VN/14-1 in the blood over time in rats. They found that the amount of VN/14-1 in the blood after oral administration was exceptionally high compared to intravenous VN/14-1. This indicates that VN/14-1 should be tested orally as this is the preferred route of drug administration in humans, Njar says. "Giving an agent orally in small doses is exactly what you want in an anti-cancer drug," he said.

The study was funded by grants from the National Institutes of Health and National Cancer Institute, the U.S. Department of Defense, and UMB's Marlene and Stewart Greenebaum Cancer Center.