To find out, Rosenblum designed an experiment with VEGF121/rGel, an agent he and his colleagues began to develop several years ago. They created the drug by fusing the smallest of VEGF proteins (VEGF 121) to a genetically engineered toxin, gelonin, derived from a plant that grows wild in India, and used bacteria to produce the fusion protein. The agent is designed to enter new blood vessel cells in tumors through expressed VEGF receptors and, once inside, the "Trojan Horse" toxin destroys the cell, disrupting the ability of tumors to form blood vessels to supply the nutrients they need to grow. Animal studies previously conducted by the researchers have shown that the protein can selectively destroy blood vessels feeding human solid tumors.
In this study, investigators implanted human prostate cancer cells, which are highly metastatic to bone, directly into the leg bone marrow of experimental mice in order to simulate a bone metastasis. A week later, they treated the animals with five staggered doses of VEGF121/rGel delivered through intravenous injections.
Half of the treated mice did not develop any bone tumors, Rosenblum says. "There was no evidence of cancer growth," he says, adding, "We don't know why the treatment didn't work in the other half of the mice, but we may have started therapy too late."
Rosenblum and his research team then found that VEGF121/rGel dramatically reduced the number of osteoclast cells in the leg bones and further research demonstrated that pre-osteoclast like cells, known as monocytes, had been expressing a receptor, Flt-1, designed to latch on to the VEGF protein secreted by cancer cells.
When activated by maturation factors including VEGF, the pre-osteoclasts differentiated into mature osteoclasts and chew up bone tissue, providing the tumor new space to grow. The mature osteoclast cells themselves do not ex
Source:University of Texas M. D. Anderson Cancer Center