University of Tokyo: New anticancer drug targets low-oxygen environment of solid tumors
The mininucleic acid drug (chain of green circles, blue pentagons and beige hexagons) has protective caps (dark pink) that degrade only in the low-oxygen environment characteristic of malignant tumors. Upon entry into malignant tumor tissue, the protective cap degrades, and further degradation by intracellular enzymes releases the anticancer agent floxuridine. © Akimitsu Okamoto CC BY 4.0
Researchers are perfecting a new generation of anticancer drugs that will be able to specifically target the low-oxygen environment of solid tumors. So far, the new drug has been tested in preliminary experiments with human tumors transplanted into otherwise healthy adult mice.
Low oxygen levels among the densely packed cells of solid tumors serve as a convenient marker to distinguish between healthy and diseased cells. By directly targeting low-oxygen environments, researchers hope to avoid the side effects of current chemotherapy and radiation treatments.
A research team led by Professor Akimitsu Okamoto at the Research Center for Advanced Science and Technology designed the new drug, known as oligomerized nucleosides, which has the structure of a short chain of molecules similar in shape to genetic material, like RNA and DNA. The specific nucleosides used to make this drug contain floxuridine residues, which are currently used in some standard chemotherapy drugs.
“When our medicine was added to human lung tumor cells, it showed anticancer activity only under low-oxygen concentration conditions, and it effectively suppressed the growth of solid tumors simply by intravenous injection,” said Okamoto.
These new short-chain floxuridine oligomers are active only to low-oxygen areas because they are surrounded by protective molecules that act as oxygen-sensitive packaging. In healthy cells, the protective packaging remains intact and the drug has no effect. Only when the drug enters a cell with low oxygen levels does the packaging degrade, freeing the floxuridine oligomers to start enzymatic reactions that cause the cell to die.
“Tumor growth was significantly inhibited in mice injected with the drug compared to the group that did not receive the drug,” said Okamoto.
The experiments used cancer cells commonly grown in research laboratories, human lung cancer A549 cells. Clumps of the cells were injected under the mice’s skin and allowed to grow until they were 100 cubic millimeters, or about the size of a peanut. The mice then received injections of the drug every 72 hours for a total of three doses. Researchers then monitored the size of their tumors for the next two weeks. In mice who received the drug, tumors grew 2.5 times less than the tumors in mice who received no treatment. The mice did not change their behavior, lose weight or have changes in their blood test results during the treatment, indicating they experienced no side effects.
Researchers hope to achieve more dramatic tumor suppression in the future by continuing to perfect the drug.
“Our future work will include the optimization of the length of floxuridine oligomers and the pattern of protective molecules,” said Okamoto.
This research is a peer-reviewed experimental study in human cells and mice published in the Journal of the American Chemical Society.