Researchers at Boston University School of Medicine have discovered that small DNA fragments or oligonucleotides that resemble the telomere (chromosome end), also called T-oligos, can cause human melanoma cells to undergo extensive apoptosis (cell death), while surviving melanoma cells become more differentiated and therefore less aggressive.
The results, which appear in the September 2004 FASEB Journal, suggest a new treatment for melanoma, a disease responsible for more than 50,000 new skin cancer cases and more than 7,500 deaths per year in the United States.
Led by Barbara Gilchrest, MD, chairman and professor of dermatology at BUSM, researchers studied the effects of T-oligos on aggressive human MM-AN melanoma cells on mice with weakened immune systems. They found brief exposure of the melanoma cells to T-oligos prior to injection into the mice reduced eventual tumor volume and number of metastases by 85 – 95 percent. In mice with previously established tumors in the flank and abdominal cavity, injection of T-oligos inhibited melanoma growth by 85-90 percent in both sites, without detectable toxicity for normal tissue. Melanoma cells that survived the T-oligo treatment were also less aggressive and highly differentiated compared to the same cells in control mice. There was no apparent toxicity of the treatment for normal tissues.
“Melanoma is a dread disease, resistant to all treatment modalities now available once it has spread beyond the skin,” said Gilchrest. “Our results are encouraging and we are very hopeful this finding will provide a novel means of treating melanoma.”
Research shows normal cells that undergo DNA damage have a protective mechanism that will cause severely damaged cells to self-destruct. In malignant cells, such as melanoma, the protective mechanism appears to be disabled. Gilchrest and her colleagues have previously found that T-oligos provided to cells in culture or injected into tissue can reconstitute or substitute for the mechanism causing malignant cells to destroy themselves.
The same group of investigators also showed a T-oligo, working through the same pathways, can be used to prevent skin cancer development following UV exposure in a hairless mouse model. By topically applying T-oligo to UV exposed mice intermittently over several months, researchers reduced the proportion of mice developing tumors more than six-fold and greatly delayed tumor onset, compared to control animals.
Melanoma incidence has increased more than 20-fold over the past century, likely due to increased sun exposure, particularly intermittent intense sun exposure. It is estimated that one in 70 Americans born today will develop melanoma in their lifetime.