Inducing eye-tumor cells to self-destruct

From Washington, D.C., at a seminar on Research to Prevent Blindness

When their usefulness has ended, most cells succumb to a natural process of programmed cell death called apoptosis. The cells break up and their constituents are recycled.

In contrast, tumor cells don’t know when to die, thereby exacerbating the uncontrolled growth of malignancies. By reawakening the apoptosis that seems to fail in many tumor cells, J. William Harbour, an ophthalmologist at Washington University School of Medicine in St. Louis, and his colleagues have now found a way to stop the progress of two eye cancers in cell cultures and rabbits.

His group focused on a key apoptosis-inducing compound, the protein called p53. In two eye cancers, uveal melanoma and retinoblastoma, p53 is rendered unable to induce apoptosis. In the body, p53 has a natural regulator, called HDM2, which keeps p53’s effectiveness low until a cell signals unusual growth or other DNA irregularities.

Then, HDM2 normally backs off, opening the way for p53 production to rev up and stimulate the manufacture of apoptosis-inducing chemicals. In eye-cancer cells, however, HDM2 doesn’t step back. Instead, it relentlessly thwarts p53.

To induce apoptosis in cancer cells, Harbour and his colleagues synthesized a miniprotein resembling part of p53. They took advantage of studies elsewhere of the human immunodeficiency virus that revealed that it makes a protein, called TAT, that can pass through cell membranes effortlessly. The scientists attached the p53 miniprotein to TAT for delivery into cells.

In the test tube, this combination binds to HDM2 and stops it from inhibiting the full p53. In the presence of the synthetic miniprotein, the unfettered p53 induces apoptosis in both types of cancer cells in a lab dish but not in normal cells, says Harbour.

The researchers next injected the HDM2-blocking treatment into the eyes of a rabbit with retinoblastoma. Within 48 hours, three-fourths of tumor cells in the animal began to undergo apoptosis, while healthy cells remained unaffected.

A TAT-based drug would probably also work as an eye drop, Harbour says, since it could pass through the cornea.


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