PURPOSE: Although the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine (FdCyd), is being evaluated clinically, it must be combined with the cytidine deaminase inhibitor tetrahydrouridine (THU) to prevent rapid metabolism of FdCyd to the pharmacologically active, yet unwanted, metabolites 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluorouracil (FU), and 5-fluorouridine (FUrd). We assessed plasma concentrations of FdCyd and metabolites in patients receiving FdCyd and THU. METHODS: We validated an LC-MS/MS assay, developed for a preclinical study, to quantitate FdCyd and metabolites in human plasma. Patients were treated with five daily, 3-h infusions of FdCyd at doses of 5-80 mg/m(2) with 350 mg/m(2) THU. Plasma was obtained during, and before the end of infusions on days 1 and 5. RESULTS: The lower limits of quantitation for FU, FdUrd, FUrd, FC and FdCyd were 1, 1.5, 10, 3, and 10 ng/ml, respectively. Plasma FdCyd increased with dose, from 19-96 ng/ml at 5 mg/m(2) to 1,600-1,728 ng/ml at 80 mg/m(2). FdUrd was undetectable in patients treated with FdCyd doses <20 mg/m(2), and increased from 2.3 ng/ml at 20 mg/m(2) to 3.5-5.7 ng/ml at 80 mg/m(2). FU increased from 1.2-5.5 ng/ml at 5 mg/m(2) to 6.0-12 ng/ml at 80 mg/m(2). CONCLUSIONS: By co-administering FdCyd with THU, FdCyd plasma concentrations were achieved that are known to inhibit DNA methylation in vitro. The accompanying plasma FU and FdUrd concentrations are <10% those observed after therapeutic infusions of FU or FdUrd, while FdCyd levels are well above those required to inhibit methylation in vitro. Therefore, inhibition of DNA methylation with FdCyd and THU appears feasible.
PURPOSE: Although the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine (FdCyd), is being evaluated clinically, it must be combined with the cytidine deaminase inhibitor tetrahydrouridine (THU) to prevent rapid metabolism of FdCyd to the pharmacologically active, yet unwanted, metabolites 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluorouracil (FU), and 5-fluorouridine (FUrd). We assessed plasma concentrations of FdCyd and metabolites in patients receiving FdCyd and THU. METHODS: We validated an LC-MS/MS assay, developed for a preclinical study, to quantitate FdCyd and metabolites in human plasma. Patients were treated with five daily, 3-h infusions of FdCyd at doses of 5-80 mg/m(2) with 350 mg/m(2) THU. Plasma was obtained during, and before the end of infusions on days 1 and 5. RESULTS: The lower limits of quantitation for FU, FdUrd, FUrd, FC and FdCyd were 1, 1.5, 10, 3, and 10 ng/ml, respectively. Plasma FdCyd increased with dose, from 19-96 ng/ml at 5 mg/m(2) to 1,600-1,728 ng/ml at 80 mg/m(2). FdUrd was undetectable in patients treated with FdCyd doses <20 mg/m(2), and increased from 2.3 ng/ml at 20 mg/m(2) to 3.5-5.7 ng/ml at 80 mg/m(2). FU increased from 1.2-5.5 ng/ml at 5 mg/m(2) to 6.0-12 ng/ml at 80 mg/m(2). CONCLUSIONS: By co-administering FdCyd with THU, FdCyd plasma concentrations were achieved that are known to inhibit DNA methylation in vitro. The accompanying plasma FU and FdUrd concentrations are <10% those observed after therapeutic infusions of FU or FdUrd, while FdCyd levels are well above those required to inhibit methylation in vitro. Therefore, inhibition of DNA methylation with FdCyd and THU appears feasible.
Authors: Donald Lavelle; Kestis Vaitkus; Yonghua Ling; Maria A Ruiz; Reda Mahfouz; Kwok Peng Ng; Soledad Negrotto; Nicola Smith; Pramod Terse; Kory J Engelke; Joseph Covey; Kenneth K Chan; Joseph Desimone; Yogen Saunthararajah Journal: Blood Date: 2011-12-07 Impact factor: 22.113
Authors: Jan H Beumer; Julie L Eiseman; Judith A Gilbert; Julianne L Holleran; Archibong E Yellow-Duke; Dana M Clausen; David Z D'Argenio; Matthew M Ames; Pamela A Hershberger; Robert A Parise; Lihua Bai; Joseph M Covey; Merrill J Egorin Journal: Cancer Chemother Pharmacol Date: 2010-05-05 Impact factor: 3.333
Authors: Edward M Newman; Robert J Morgan; Shivaani Kummar; Jan H Beumer; M Suzette Blanchard; Christopher Ruel; Anthony B El-Khoueiry; Mary I Carroll; Jessie M Hou; Chun Li; Heinz J Lenz; Julie L Eiseman; James H Doroshow Journal: Cancer Chemother Pharmacol Date: 2015-01-08 Impact factor: 3.333
Authors: Jaideep V Thottassery; Vijaya Sambandam; Paula W Allan; Joseph A Maddry; Yulia Y Maxuitenko; Kamal Tiwari; Melinda Hollingshead; William B Parker Journal: Cancer Chemother Pharmacol Date: 2014-06-08 Impact factor: 3.333
Authors: Long Shan Li; Julio C Morales; Martina Veigl; David Sedwick; Sheldon Greer; Mark Meyers; Mark Wagner; Richard Fishel; David A Boothman Journal: Br J Pharmacol Date: 2009-09-23 Impact factor: 8.739
Authors: Julianne L Holleran; Julie L Eiseman; Robert A Parise; Shivaani Kummar; Jan H Beumer Journal: J Pharm Biomed Anal Date: 2016-07-18 Impact factor: 3.935