BioWorld International Correspondent
LONDON - A drug that has been investigated for treatment of cancer could turn out to have a role in the prevention of premature labor. Researchers in the UK have found that trichostatin A, an antibiotic and an antifungal drug that has been tried as a treatment for bowel and breast cancer, can control levels of a hormone receptor that prevents uterine contractions.
Nick Europe-Finner, reader in myometrial sciences at the University of Newcastle upon Tyne in the UK, told BioWorld International: "Most people who have tried to treat preterm labor have taken the approach of altering proteins that are already there. But our work has shown the potential of a completely new approach: regulating a gene in order to make the uterus relax."
Europe-Finner and his colleagues are seeking funding for clinical trials to assess whether trichostatin A would work in women who might give birth prematurely, or who are at high risk of having a premature baby.
The team fears that it may be difficult to obtain funding to test their results in the clinic, however. "After the thalidomide disaster, everyone is right to be cautious," Europe-Finner said. "But this drug would only have to be given in the third trimester of pregnancy, well after organogenesis of the fetus is complete."
An account of the study appears in the June 13, 2005, issue of the Journal of Clinical Endocrinology and Metabolism in a paper titled "Regulation of Expression of the Chorionic Gonadotropin/Luteinizing Hormone Receptor Gene in the Human Myometrium: Involvement of Specificity Protein-1 (Sp1), Sp3, Sp4, Sp-like Proteins, and Histone Deacetylases."
Each year in the UK, between 60,000 and 70,000 births occur prematurely at less than 37 weeks' gestation. That is the highest rate in Europe. Although such premature births account for only 5 percent to 7 percent of all births, they result in 60 percent to 70 percent of all perinatal deaths. Of those babies born prematurely who survive, some are permanently disabled. There is no effective treatment for preterm labor.
During pregnancy, the placenta produces the hormone human chorionic gonadotropin (hCG), which binds to its receptors in the muscle layer of the uterus - the myometrium. There, it stimulates the production of cyclic AMP, which acts as a muscle relaxant. When labor (whether preterm or term) begins, the receptors for hCG on the myometrium are down-regulated. Cyclic AMP no longer is produced and the uterus begins to contract.
In the U.S., researchers working on choriocarcinoma cell lines had investigated the regulation of hCG receptors. Europe-Finner and his team set out to discover whether the gene encoding the hCG receptor was regulated in a similar fashion in human myometrial cells.
"We thought that if it was, this would give us a handle on how we could either turn up production of the receptor to avoid preterm labor, or turn it down if you wanted contractions to begin," Europe-Finner said.
The American researchers had determined that, in order for the gene encoding the hCG receptor to be expressed in choriocarcinoma cells, the proteins around the DNA, which are called histones, become acetylated and start to loosen up, allowing the gene to be transcribed into messenger RNA.
Conversely, when the cell wants to shut down transcription of the hCG receptor, it uses enzymes called histone deacetylases, which remove the acetyl groups from the histones. As a result, the DNA and chromatin are in a closed formation, and the transcription machinery of the cell cannot gain access to the genetic code. The gene is effectively silenced.
The paper records how Europe-Finner and his colleagues confirmed that exactly the same mechanisms allow expression or silencing of the hCG receptor in myometrial cells. The UK team also showed that expression of the receptor was susceptible to trichostatin A, which inhibits the histone deacetylases.
When they added trichostatin A to myometrial cells in culture, the histones became hyperacetylated, the gene for the HCG receptor was transcribed in abundance, and the receptor itself was expressed at high levels in the cells.
Europe-Finner said: "The idea is that if you gave trichostatin A, you would up-regulate the hCG receptor in the myometrium, sensitizing the uterus to the hCG that is produced by the placenta. In theory you can then have myometrial relaxation, with no labor until you reach term, when you can remove the drug."