Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita

Abstract

Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (TERT, n = 1),in the telomerase RNA component (TERC, n = 2) and in dyskerin pseudouridine synthase 1 (DKC1, n = 1) and found no substantial differences in the activity of these three agents in patients with TERC/TERT mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased TERT expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated TERT expression, thereby underscoring the involvement of TERT in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients’ individual co-morbidities, e.g., pre-existing liver disease and expected side-effects.

Determinants of survival after lung transplantation in telomerase-related gene mutation carriers: A retrospective cohort

“…The measurement of telomere length was performed using quantitative real‐time PCR (qPCR) as previously described and expressed as telomere to single copy gene (T/S) ratio 21 …”

Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy

“…Measurement of TL was performed using the Absolute Human Telomere Length Quantification qPCR Assay Kit (ScienCell, Carlsbad, CA, USA) and FastStart Essential DNA Green Master (Roche, Basel, Switzerland). Quantitative real-time PCR (qPCR) was done with an ABI7500fast real-time PCR system (Applied Biosystems, Foster city, CA, USA) according to the Assay Kit protocol and described previously ( 26 ). TL was measured as T/S ratio.…”

Airway complications in lung transplant recipients with telomere‐related interstitial lung disease

“…Quantitative real-time polymerase chain reaction (qPCR) was done with an ABI7500fast real-time PCR system (Applied Biosystems, Foster City, CA, USA) according to the Assay Kit protocol, as previously described. 7 All bronchial anastomoses at GTP-SPLF and BWH were completed using end-to-end anastomosis without bronchial artery revascularization. Post-transplant immunosuppression included induction with solumedrol and, in some cases, a cytolytic agent (anti-thymocyte globulin) or an interleukin-2 receptor alpha antibody (IL-2RA, basiliximab), depending on the study year and institution.…”