By Sean Henahan, Access Excellence

BOSTON, MA- A team of genetic researchers has discovered a new class of regulatory genes, that could lead to new approaches in the treatment of cancer.

The genes code a class of compounds known as the CDC25 phosphatases. Knowing that these enzymes were involved in the process of cell division in normal cells (causing the cells to replicate their DNA before dividing), the researchers hypothesized a potential role for the enzymes in cancer.

The first step in testing the hypothesis involved experiments with mouse cells. The researchers introduced CDC25 genes into normal mouse embryo fibroblasts. The cells were transfected with these plasmids alone, or in combination with known oncogenes (RAS) and grown on culture. Subsequent inspection revealed evidence of successful transfection and cell transformation.

These potentially tumorigenic cells were then introduced into test mice. After 20 to 25 days all of the animals injected with the CDC25/oncogene transformed cells developed tumors. Mice injected with cells transfected with either CDC25 or RAS oncogene alone did not develop tumors. Mutations in RAS are known to coincide with mutations in the tumor suppressor genes p53 and RB1.

This led the researchers to test the idea of whether mutant forms of these tumor suppressor genes might be susceptible to the oncogenic effects of CDC25. In test mice lacking the tumor suppressor RB1, expression of two of the three human CDC25 genes resulted in high-grade tumors.

This led the researchers to study the effect of CDC25 genes in cells lines derived from human tumors. Sure enough, an over-abundance of CDC25B protein showed up in 32 percent of 124 human breast cancers studied while also correlating with lower survival. Patients whose cancer cells expressed high levels of CDC25B had significantly higher recurrence rates than those with little or no CDC25B expression.

"Our results suggest that altercations in the function of CDC25A and CDC25B by overexpression might promote oncogenic transformation in vivo, and further suggest that CDC25 phosphatases (A and B) are novel potential oncogenes," the researchers reported.

CDC25 phosphatases activate cyclin-dependent kinases. These regulate the steps of cell division through each phase of the cycle. Human CDC25 genes function at the G1 or S phase, and at the G2 or M phase. There are three different human CDC25 genes (A, B,C) which are closely related.

The researchers are hopeful that the discovery of these genes could lead to a new way of killing cancer cells by carefully targeting hitherto unexploited phases of the cancer cell's replication cycle. The hope is that, by more specific targeting of cancer cells, normal cells would be spared. This in turn would probably reduce some of the toxic side effects of current chemotherapeutic regimens. For further information on this study, see Science, Vol. 269, 9/15/95, Galaktionov et al., pp.1575-1577.