In the 1990s, a cancer drug called TNP-470 dramatically increased life span for some patients and led to complete cancer regression in others. But when neurotoxicity was detected in some patients, clinical trials were halted. This is a common problem: many drugs that show great promise in the lab fail in clinical trials due to unforeseen toxicity. Nanomedicine, however, promises a way to make safer, more effective versions of such drugs. Researchers at Children's Hospital Boston have created and tested in mice a safer version of TNP-470.

"This is one of the first examples of nanotechnology resurrecting older drugs that we're aware of," says Piotr Grodzinski, director of the National Cancer Institute's nanotechnology programs.

The resurrected drug, which has not yet reentered clinical trials, is well proven to be one of the most potent inhibitors of a process key to the spread of cancer. Most cancer deaths are caused by tumors that spread throughout the body, not by the original tumor. In order for these secondary tumors, which start with a single wandering cancer cell, to become entrenched and grow large enough to become deadly, they must first establish a network of blood vessels in a process called angiogenesis. If angiogenesis can be stopped, then a patient's cancer won't be able to spread. And compared with traditional chemotherapy and radiation, angiogenesis inhibitors have few side effects. The Children's Hospital drug, called Lodamin in its nanoformulation, is "the most generic and potent angiogenesis inhibitor ever seen," says Don Ingber, a professor of vascular biology at Harvard Medical School.

Ingber discovered the drug by accident in 1985, when he was a postdoc in the lab of Children's Hospital researcher Judah Folkman. Ingber noticed that lab-grown blood-vessel cells accidentally contaminated with a fungus weren't growing very well; an analog of the responsible fungal compound, TNP-470, was made by Takeda Pharmaceutical Company and extensively tested in animals. These studies suggested that it would prevent blood-vessel growth in a wide range of tumor types. Early-stage clinical trials of the compound were promising. In patients with lung cancer, says Ingber, the drug led to a 50 percent increase in life expectancy. But in some patients, the drug was a neurotoxin, causing confusion and dizziness and, in a few cases, more-serious problems. Just as TNP-470 was about to enter late-stage clinical trials, the company faced a lawsuit and stopped testing the drug.

But Folkman's lab didn't forget about TNP-470, even after another anti-angiogenesis drug, called Avastin, became a blockbuster. Avastin stops only one of the triggers of blood-vessel formation; TNP-470 works through an unknown mechanism but appears to target multiple parts of the process and, in animal studies, works in more tumor types. This broad activity suggests that it may work in more people, and that it should be difficult for tumors to become resistant to the drug. A few years ago, Folkman's group modified TNP-470 to prevent neurotoxicity by attaching a large polymer that prevents the compound from crossing the blood-brain barrier. This version, however, must be given intravenously--a patient would have to return to the hospital again and again for treatments to prevent cancer recurrence.

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Special delivery: This blood-vessel cell--the same type of cell that feeds spreading tumors--has absorbed a newly formulated cancer drug. In this fluorescence image, the cell’s structural elements are labeled red, the nucleus is labeled blue, and a cancer drug encased in a polymer envelope is labeled green.
Credit: Ofra Benny, Children’s Hospital Boston