A small prospective study published on May 19, 2016, in NEJM says that Danazol, the synthetic analog of male hormone, can preserve valuable genetic material that can be lost with each cell division due to the shortage of telomeres.
The researchers found that Danazol protects genetic material by regulating expression of the telomerase gene. Telomeres are the protective ending of the chromosomes that preserve genetic information at the time of cell division. Telomere shortening is the part of normal aging. Telomerase is the enzyme that prevents shortening of telomeres and ensures that cells keep dividing normally. Mammalian tissues lack telomerase, so the shortening of telomeres is inevitable.
Besides increasing susceptibility to cancer, genetic defects in telomere regulation lead to a myriad of disorders including pulmonary fibrosis, liver cirrhosis and bone marrow failure. Danazol, in past, has also been successfully used in the treatment of marrow failure syndrome.
The successful employment of the drug in bone marrow-related diseases sparked curiosity amongst researchers who decided to evaluate the beneficial effects of Danazol, if any, in telomere maintenance and repair. The results were promising.
The prospective study enrolled 27 patients, aged two years and older, with telomerase diseases. All patients had:
- Telomere length at or below first percentile
- Documented mutations in telomerase gene
The patients were given Danazol (800 mg, twice daily) for a prolonged period i.e., two years, since the study aimed to investigate the long-term effects of the drug. The dose was titrated or discontinued if the patient developed adverse effects of grade 3 or 4.
The primary end point of the study was telomere attrition. The normal rate of telomere attrition is 60 bp/year, for the sake of the study, the telomere attrition was conservatively estimated at 120 bp/year.
At the end of the two-year period, leukocyte samples were withdrawn from the patients and genomic DNA was purified from the blood cells. Telomere length was then determined individually.
Surprisingly, all patients showed an increase in telomere length. The results began to manifest as soon as six months and one year of Danazol therapy. The drug showed consistency in improving telomere length as long as it was used.
As for the side effects of the drug, adverse effects of grade two or less occurred in 19 out of 24 patients evaluated at 3 months, and in 10 out of 12 patients evaluated at 24 months. The side effects included muscle cramps and elevated liver-enzyme cells.
The researchers concluded that Danazol successfully leads to telomere elongation in patients either susceptible to or having an active telomere disease.
Mutations could not be identified in all patients.
Repeated measurement of telomere length could lead to telomere fluctuations and affect the outcome.
Telomere Diseases And Danazol
Located at the end of chromosomes, telomeres are hexanucleotides where they serve to protect the ends of chromosomes. In the absence of telomeres, the DNA will identify chromosomes as infectious or damaged.
With each cell division, telomeres undergo a reduction in size. This can lead to the loss of valuable genetic information. Unless it wasn’t for the enzyme – called telomerase – accounting for telomeres maintenance and repair, telomere shortening can lead to the loss of valuable genetic information.
In telomere diseases, mutations in the genes coding for telomerase occur that affect the repair and maintenance of the chromosome caps. This loss results in a number of diseases such as various types of cancers, pulmonary fibrosis, liver cirrhosis and bone marrow failure.
Danazol – or the synthetic replica of male hormone called androgen – has successfully been used in the treatment of bone marrow failures since 20th century.