Oral decitabine reactivates expression of the methylated γ‐globin gene in Papio anubis

Abstract

The silencing of tumor suppressor genes associated with increased DNA methylation of the promoter regions is a frequent observation in many forms of cancer. Reactivation of these genes using pharmacological inhibitors of DNA methyltransferase such as 5-aza-29-deoxycytidine (decitabine) is a worthwhile therapeutic goal. The effectiveness and tolerability of low-dose intravenous and subcutaneous decitabine regimens to demethylate and reactivate expression of the methylated c-globin gene in baboons and in patients with sickle cell disease led to successful trials of low-dose regimens of this drug in patients with myelodysplastic syndrome. Since these low-dose regimens are well-tolerated with minimal toxicity, they are suitable for chronic dosing to maintain promoter hypomethylation and expression of target genes. The development of an orally administered therapy using DNA methyltransferase inhibitors would facilitate such chronic approaches to therapy. We tested the ability of decitabine and a new salt derivative, decitabine mesylate, to reactivate the methylated c-globin gene in baboons when administered orally. Our results demonstrate that oral administration of these drugs at doses 17-34 times optimal subcutaneous doses of decitabine reactivates fetal hemoglobin, demethylates the e e-and c-globin gene promoters, and increases histone acetylation of these promoters in baboons (Papio anubis). Am. J. Hematol. 82:981-985, 2007.

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

“…Comparison of the level of γ-globin synthesis in RN-1-treated baboons with previous results from our laboratory of baboons treated with DNMT inhibitors [3][4][5]12,38,[40][41][42] A. Rivers et al 694 haematologica | 2016; 101(6) …”

DNA Methyltransferase and Histone Deacetylase Inhibitors in the Treatment of Myelodysplastic Syndromes

“…(19). By contrast, studies in baboons using oral decitabine and decitabine mesylate achieved similar re-expression of fetal hemoglobin to that observed with subcutaneously administered DAC, suggesting that these agents may be more effectively absorbed (20). As yet there are no published reports for these orally administered drugs in humans.…”

Activity of a Novel Combined Antiretroviral Therapy of Gemcitabine and Decitabine in a Mouse Model for HIV-1

“…However, Eli Lilly has developed a gemcitabine prodrug that is currently in clinical trials. Although no decitabine prodrugs are currently in clinical trials, it has been demonstrated that with appropriate oral dosing, it is possible to achieve pharmacologically relevant plasma concentrations for cancer treatment (17). Since the dose of decitabine needed to inhibit HIV replication is expected to be lower, it is possible that a prodrug would not be needed, although without a prodrug, it is likely that decitabine would have to be taken multiple times per day, which is not reasonable for anti-HIV drugs.…”