A Potential Novel Therapeutic Approach for Fanconi Anemia

Lymphoblastoid cells from normal subjects and from patients with the bone marrow failure and cancer prone inherited disease, Fanconi anemia (FA) were treated in culture with psoralen plus ultraviolet A radiation (PUVA) in a scheme shown to produce interstrand crosslinks in cellular DNA. Hypersensitivity to DNA interstrand crosslinks, with associated increased clastogenicity, is considered to be a diagnostic hallmark of the disease. Following this cells were treated with hydroxyurea, 5 fluorouracil, or high dose thymidine for 24 hours. Clastogenicity and cytotoxicity, measured as trypan blue exclusion, were then found to be markedly increased in FA cells but not in FA cells subsequently treated with any of these other agents. Similar results were also found when all drugs were removed after these treatments and the cells cultured for 10 days without any drug in colony forming ability assays. We propose that the mechanism is related to decrease in the rate of DNA synthesis, which we have shown occurs in normal but not FA cells following PUVA, and which is also produced by these other drugs in the concentrations used here. Hydroxyurea has been used for many years as a safe and effective treatment for sickle cell anemia. It is now proposed as a possible treatment for Fanconi anemia to delay or even prevent development of bone marrow failure and/or other complications, including leukemogenesis and carcinogenesis, with or without prior bone marrow transplantation.