HMS Researchers Use New Technique To Cure Cancer in Mice

A group of Harvard researchers at Boston Children's Hospital say they have cured cancer in mice by applying new methodology to a standard cancer treatment--chemotherapy.

In the April 1 issue of the journal Cancer Research, Dr. Timothy M. Browder, an oncologist and Harvard instructor in pediatrics at the Children's Hospital, and a group of his colleagues presented data from a five-year study which sought to examine the effect of targeting a tumor's blood supply rather than the tumor directly.

The data give statistical support to a long-suspected theory that cutting off a tumor's blood supply may shrink it. The article reports that when lower doses of traditional chemotherapy drugs were given more frequently to inhibit blood cell growth--known as angiogenesis--in test mice, 100 percent of drug-sensitive tumors were cured.

In mice whose cancer had become resistant to traditional chemotherapy schedules, the new treatment regimen was three times as effective as the standard regimen in suppressing tumor growth. The standard regimen entails higher doses of chemotherapy drugs, administered less frequently.

"The bottom line is that it's old drugs, new logic," said Harvard Medical School's Andrus Professor of Pediatric Surgery M. Judah Folkman, who heads the laboratory where the study was conducted.

The study also examined the effect of combining the traditional chemotherapy drugs with an experimental drug that attacks the tumor's blood supply. According to the report, 84 percent of mice with tumors that were unresponsive to traditional chemotherapy drugs were cured when the standard chemotherapy drug was combined with a low dose of an angiogenesis inhibitor.

The inhibitor, TNP-470, doesn't attack the tumor itself but instead targets the blood vessels.

Because the tumors in question had been unresponsive to the traditional chemotherapy treatment, Folkman said, the study lends support to the theory that it is possible to halt and reverse cancer growth in mice with a "flanking maneuver"--targeting blood cells surrounding the tumor but not the tumor itself.

"It provides additional evidence that tumors are angiogenesis-dependent, evidence for which has been piling up for 30 years now," Folkman said.

Folkman said the findings suggest a new way to treat tumors that were thought to be untreatable because they were resistant to traditional chemotherapy drug treatments.

He said some angiogenesis inhibitors are currently in clinical trials and may be added to conventional chemotherapy treatments in clinical studies when and if they are approved by the Food and Drug Administration.

The results of the study are particularly important to Folkman and members of his laboratory team, who have been studying angiogenesis for about 30 years.

In 1995, Browder, who was working full-time in Folkman's laboratory, began experimenting with non-standard treatment regimens that utilized a standard chemotherapy drug, Cytoxan. He eventually developed a treatment schedule that appeared to inhibit the regeneration of endothelial cells--the cells that line blood vessels--in test mice.

The treatment schedule consisted of a lower total dose of drugs administered continually every six days.

Conventional chemotherapy treatment typically gives patients high doses of toxic drugs to kill cancer cells and then prescribes a recovery period in which no drugs are administered.

Browder discovered that the off-therapy period allows the blood cells that feed tumors to regenerate and continue to nourish the very cancer cells that chemotherapy seeks to destroy.

For example, a standard treatment schedule for a woman with breast cancer might be to blast the cancer cells with the maximum dose of chemotherapy drugs she can stand, then allow her to rest for three weeks while her body recuperates, Folkman said.

"Conventional philosophy is to try to kill all the tumor cells early,"

Folkman said. "But you're forced to stop and rescue the bone marrow."

During the intensive drug treatment, cancer cells and surrounding tissue die off. But when the drugs are taken away for even a few weeks, endothelial cells can grow back.

In a statement issued March 31, Browder explained that unlike cancer cells, which tend to quickly divide and mutate, endothelial cells "are not themselves cancerous and thus are much less likely to develop resistance to chemotherapy."

In addition, giving lower doses of the standard drug proved "more effective and less toxic" in mice, the statement said.

Browder and Folkman's data point cancer researchers in a promising direction, especially because their evidence has been corroborated by other researchers who have conducted similar experiments.

Robert S. Kerbel, a professor of medical biophysics at the University of Toronto, published results in the Journal of Clinical Investigation that supported Browder's study.

Kerbel, who has collaborated with the Folkman laboratory for several years, used different chemicals than Browder but employed a similar technique in his study.

"[Kerbel] has said publicly that he got the idea from Dr. Browder, and it's nice to have it repeated," Folkman said.

But the researchers have said that despite the promising findings, they are cautiously optimistic, in part because the study only used mice as its subjects.

"It's an important paper, but it's not for immediate application," Folkman said. "The clinical trials will prove whether you will be able to use chemotherapy in that mode to help people. That's the practical application that hasn't been proved yet."