NEW ORLEANS--Researchers at the Dana-Farber Cancer Institute have
initiated a trial of an angiogenesis inhibitor in children with
recurrent solid tumors, the idea being to stunt the growth of
new blood vessels that nourish the tumor. Speaking at the American
Cancer Society Science Writers Seminar, Dr. Stephen Skapek, of
the Department of Pediatrics, Harvard, said that an agent known
as TNP-470 (formerly AGM-1470) was found to be a "potent"
inhibitor of blood vessel growth in immunosuppressed mice and
produced a desirable adverse effects profile.
Based on these preclinical results, a phase I study was begun
to assess the pharmacokinetics and safety of TNP-470 in 30 patients,
aged 2 to 20 years. Three children have been enrolled to date,
with diagnoses of recurrent medulloblastoma, CNS sarcoma, and
Ewing's sarcoma. They will be given the agent intravenously three
times a week and assessed at 8 weeks.
Dr. Skapek and his colleagues are particularly interested in the
drug's effect on brain tumors. Despite recent therapeutic advances,
fewer than 50% of children with brain tumors are cured; therefore,
the search for novel agents to treat these children remains a
high priority, he said.
The mechanism of action of TNP-470 is unclear (see below). Dr.
Skapek said the drug was developed when fumagillin, a similar
naturally occurring chemical made by Aspergillus, was "serendipitously"
found to be a potent inhibitor of new blood vessel growth.
Although TNP-470 and fumagillin are chemically similar, TNP-470
is more potent and has fewer side effects than its biological
cousin, and is more potent than other analogs to which it has
been compared in cell cultures, he said.
Laboratory animals receiving the drug demonstrated mild weight
loss, mild suppression of white blood cells and platelets, and
mild evidence of microscopic hemorrhage in various tissues.
Fortunately, the blockage of angiogenesis does not interfere with
the efficacy of chemotherapeutic agents, which depend upon blood
flow for delivery. "Preclinical studies are showing that
you actually get increased delivery of cytotoxic drugs to the
tumor when you use TNP-470," Dr. Skapek said. "By inhibiting
new blood vessel formation, the agent seems to decompress existing