Gunnar Boysen1,2, Avichai Shimoni3, Ivetta Danylesko3, Nira Varda-Bloom3, Arnon Nagler3. 1. Department of Environmental and Occupational Health, The University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. 2. The Winthrop P. Rockefeller Cancer Institute, The University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. 3. Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Abstract
RATIONALE: Treosulfan is a substance that is being studied as part of the conditioning regimen given prior to allogeneic stem cell transplantation in patients with hematological malignancies. It is known to decompose into 1,2:3,4-diepoxybutane (DEB) under physiologic conditions. In this study, we investigate whether N-terminal valine adducts can be utilized to monitor differences in DEB formation of patients receiving treosulfan as part of the conditioning regimen for transplantation. METHODS: Blood samples were collected from a group of 14 transplant recipients and analyzed for N,N-(2,3-dihydroxy-1,4-butadiyl)valine (pyr-Val) and 2,3,4-trihydroxybutylvaline (THB-Val) adducts as biomarkers for drug uptake and metabolism before treosulfan treatment and 6 days after treatment. RESULTS: A new direct injection liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated prior to clinical analysis. The assay precision was determined by 3 replicate analyses on 3 individual days using control globin spiked with known amounts of pyr-Val and THB-Val. The intra- and inter-day precision coefficients of variance (CVs) and accuracy were < 10% and 15%, respectively. In clinical specimens, the means ± SD of pyr-Val and THB-Val background were 0.29 ± 0.10 pmol/g HB and 5.17 ± 1.7 pmol/g HB, respectively. CONCLUSIONS: These values are similar to those found previously. Treosulfan treatment leads to a significant increase in pyr-Val and THB-Val adducts in each patient (Student's t-test p <0.0001). The mean ± SD amounts of adduct formed were 245.3 ± 89.6 and 210 ± 78.5 pmol/g globin for pyr-Val and THB-Val, respectively. Importantly, these results show that this direct injection method can quantitate both background and treosulfan-induced pyr-Val and THB-Val N-terminal valine globin adducts in humans.
RATIONALE: Treosulfan is a substance that is being studied as part of the conditioning regimen given prior to allogeneic stem cell transplantation in patients with hematological malignancies. It is known to decompose into 1,2:3,4-diepoxybutane (DEB) under physiologic conditions. In this study, we investigate whether N-terminal valine adducts can be utilized to monitor differences in DEB formation of patients receiving treosulfan as part of the conditioning regimen for transplantation. METHODS: Blood samples were collected from a group of 14 transplant recipients and analyzed for N,N-(2,3-dihydroxy-1,4-butadiyl)valine (pyr-Val) and 2,3,4-trihydroxybutylvaline (THB-Val) adducts as biomarkers for drug uptake and metabolism before treosulfan treatment and 6 days after treatment. RESULTS: A new direct injection liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated prior to clinical analysis. The assay precision was determined by 3 replicate analyses on 3 individual days using control globin spiked with known amounts of pyr-Val and THB-Val. The intra- and inter-day precision coefficients of variance (CVs) and accuracy were < 10% and 15%, respectively. In clinical specimens, the means ± SD of pyr-Val and THB-Val background were 0.29 ± 0.10 pmol/g HB and 5.17 ± 1.7 pmol/g HB, respectively. CONCLUSIONS: These values are similar to those found previously. Treosulfan treatment leads to a significant increase in pyr-Val and THB-Val adducts in each patient (Student's t-test p <0.0001). The mean ± SD amounts of adduct formed were 245.3 ± 89.6 and 210 ± 78.5 pmol/g globin for pyr-Val and THB-Val, respectively. Importantly, these results show that this direct injection method can quantitate both background and treosulfan-induced pyr-Val and THB-ValN-terminal valine globin adducts in humans.
Authors: Nadia I Georgieva; Gunnar Boysen; Narisa Bordeerat; Vernon E Walker; James A Swenberg Journal: Toxicol Sci Date: 2010-02-22 Impact factor: 4.849
Authors: Gunnar Boysen; Nadia I Georgieva; Narisa K Bordeerat; Radim J Sram; Pamela Vacek; Richard J Albertini; James A Swenberg Journal: Toxicol Sci Date: 2011-10-14 Impact factor: 4.849
Authors: James A Swenberg; Narisa K Bordeerat; Gunnar Boysen; Sujey Carro; Nadia I Georgieva; Jun Nakamura; John M Troutman; Patricia B Upton; Richard J Albertini; Pamela M Vacek; Vernon E Walker; Radim J Sram; Melissa Goggin; Natalia Tretyakova Journal: Chem Biol Interact Date: 2010-10-23 Impact factor: 5.192
Authors: Hans von Stedingk; Anna C Vikström; Per Rydberg; Marie Pedersen; Jeanette K S Nielsen; Dan Segerbäck; Lisbeth E Knudsen; Margareta Törnqvist Journal: Chem Res Toxicol Date: 2011-09-15 Impact factor: 3.739
Authors: N J van Sittert; P J Boogaard; A T Natarajan; A D Tates; L G Ehrenberg; M A Törnqvist Journal: Mutat Res Date: 2000-01-17 Impact factor: 2.433
Authors: Gunnar Boysen; Rashi Arora; Amanda Degner; Karin R Vevang; Christopher Chao; Freddys Rodriguez; Scott J Walmsley; Luke Erber; Natalia Y Tretyakova; Lisa A Peterson Journal: Chem Res Toxicol Date: 2020-12-31 Impact factor: 3.739