More efficient and safer

Cancer cells actively absorb the amino acid glutamine, which is an essential building block for proteins, lipids and nucleotides, as well as for the formation of energy. But other healthy tissues with rapid metabolism, including the cells lining the intestine, also depend on glutamine.

Antitumor experimental drug DON (6-Diazo-5-Oxo-L-norleucine) is a glutamine antagonist and inhibits many enzymes that utilize glutamine in cancer cells. Several studies have shown that DON is highly effective in mice and humans, but the project to develop it was closed due to toxicity to normal tissues, especially the intestines.

The researchers attached chemical groups to DON, which made it inactive in the body until it reaches the tumor, where the inactivating groups are cut off by cancer cell enzymes. This specific prodrug design was named DRP-104.

Structural formulas of glutamine, DON, DRP-104 and the metabolite DRP-104 M1.

In experiments, the original drug DON and the improved drug DRP-104 were injected into mice with solid tumors. DRP-104 accumulated in the tumor tissue in 11 times more active form than in the intestine.

Both drugs completely destroyed cancer, but DON caused greater intestinal toxicity in mice than DRP-104.

DRP-104 is currently undergoing clinical trials (phase 1-2) for patients with late-stage solid tumors at medical facilities throughout the United States, including Johns Hopkins Cancer Center.

Barbara Slusher and her colleagues will continue to search for drugs that have not passed clinical trials due to high toxicity in order to apply the same technique to create a safer precursor form.

Article R.Rais et al. The discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug is published in the journal Science Advances.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru According to Johns Hopkins University: Johns Hopkins Researchers Design 'Prodrug' That Targets Cancer Cells' Big Appetite for Glutamine, Leaving Healthy Cells Unharmed.