Characterization and quantitation of busulfan DNA adducts in the blood of patients receiving busulfan therapy

Valeria Guidolin; Yupeng Li; Foster C. Jacobs; Margaret L. MacMillan; Peter W. Villalta; Stephen S. Hecht; Silvia Balbo

doi:10.1016/j.omto.2023.01.005

Characterization and quantitation of busulfan DNA adducts in the blood of patients receiving busulfan therapy

Valeria Guidolin, Yupeng Li, Foster C. Jacobs, Margaret L. MacMillan, Peter W. Villalta, Stephen S. Hecht, Silvia Balbo

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

DNA alkylating drugs have been used as cancer chemotherapy with variable outcomes. The establishment of predictive biomarkers to identify patients who will effectively respond to treatment would allow for the development of personalized therapies. As the degree of interaction of alkylating drug with DNA plays a key role in their mechanism of action, our hypothesis is that the measurement of the DNA adducts formed by alkylating drugs could be used to inform patient stratification. Beginning with busulfan, we took advantage of our DNA adductomic approach to characterize DNA adducts formed by reacting busulfan with calf-thymus DNA. Samples collected from six patients undergoing busulfan-based chemotherapy prior to allogeneic hematopoietic cell transplantation were analyzed for the presence of busulfan-derived DNA adducts. Among the 15 adducts detected in vitro, 12 were observed in the patient blood confirming the presence of a large profile of DNA adducts in vivo. Two of the detected adducts were structurally confirmed by comparison with synthetic standards and quantified in patients. These data confirm our ability to comprehensively characterize busulfan-derived DNA damage and set the stage for the development of methods to support personalized chemotherapy.

Original language	English (US)
Pages (from-to)	197-210
Number of pages	14
Journal	Molecular Therapy Oncolytics
Volume	28
DOIs	https://doi.org/10.1016/j.omto.2023.01.005
State	Published - Mar 16 2023

Bibliographical note

Funding Information:
MS was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, University of Minnesota, supported in part by Cancer Center Support Grant CA-077598 . Salary support for P.W.V., head of the Analytical Biochemistry Shared Resource, was provided by the National Cancer Institute Grant CA-211256 . The authors would like to thank Dr. Laura Maertens and Carsten Spry for their help with initiating and coordinating the sample collection for this study. We also wish to thank the patients for their participation in this study. Additionally, we acknowledge the hard work and dedication of the nurses and other medical personnel of the M Health Fairview University of Minnesota Medical Center for their help with collecting the samples. We thank Robert Carlson for editorial assistance.

Publisher Copyright:
© 2023 The Authors

Keywords

DNA adduct
alkylating agents
biomarker
busulfan
mass spectrometry
precision medicine

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.omto.2023.01.005

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title = "Characterization and quantitation of busulfan DNA adducts in the blood of patients receiving busulfan therapy",

abstract = "DNA alkylating drugs have been used as cancer chemotherapy with variable outcomes. The establishment of predictive biomarkers to identify patients who will effectively respond to treatment would allow for the development of personalized therapies. As the degree of interaction of alkylating drug with DNA plays a key role in their mechanism of action, our hypothesis is that the measurement of the DNA adducts formed by alkylating drugs could be used to inform patient stratification. Beginning with busulfan, we took advantage of our DNA adductomic approach to characterize DNA adducts formed by reacting busulfan with calf-thymus DNA. Samples collected from six patients undergoing busulfan-based chemotherapy prior to allogeneic hematopoietic cell transplantation were analyzed for the presence of busulfan-derived DNA adducts. Among the 15 adducts detected in vitro, 12 were observed in the patient blood confirming the presence of a large profile of DNA adducts in vivo. Two of the detected adducts were structurally confirmed by comparison with synthetic standards and quantified in patients. These data confirm our ability to comprehensively characterize busulfan-derived DNA damage and set the stage for the development of methods to support personalized chemotherapy.",

keywords = "DNA adduct, alkylating agents, biomarker, busulfan, mass spectrometry, precision medicine",

author = "Valeria Guidolin and Yupeng Li and Jacobs, {Foster C.} and MacMillan, {Margaret L.} and Villalta, {Peter W.} and Hecht, {Stephen S.} and Silvia Balbo",

note = "Funding Information: MS was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, University of Minnesota, supported in part by Cancer Center Support Grant CA-077598 . Salary support for P.W.V., head of the Analytical Biochemistry Shared Resource, was provided by the National Cancer Institute Grant CA-211256 . The authors would like to thank Dr. Laura Maertens and Carsten Spry for their help with initiating and coordinating the sample collection for this study. We also wish to thank the patients for their participation in this study. Additionally, we acknowledge the hard work and dedication of the nurses and other medical personnel of the M Health Fairview University of Minnesota Medical Center for their help with collecting the samples. We thank Robert Carlson for editorial assistance. Publisher Copyright: {\textcopyright} 2023 The Authors",

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AU - Guidolin, Valeria

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AU - Jacobs, Foster C.

AU - MacMillan, Margaret L.

AU - Villalta, Peter W.

AU - Hecht, Stephen S.

AU - Balbo, Silvia

N1 - Funding Information: MS was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, University of Minnesota, supported in part by Cancer Center Support Grant CA-077598 . Salary support for P.W.V., head of the Analytical Biochemistry Shared Resource, was provided by the National Cancer Institute Grant CA-211256 . The authors would like to thank Dr. Laura Maertens and Carsten Spry for their help with initiating and coordinating the sample collection for this study. We also wish to thank the patients for their participation in this study. Additionally, we acknowledge the hard work and dedication of the nurses and other medical personnel of the M Health Fairview University of Minnesota Medical Center for their help with collecting the samples. We thank Robert Carlson for editorial assistance. Publisher Copyright: © 2023 The Authors

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N2 - DNA alkylating drugs have been used as cancer chemotherapy with variable outcomes. The establishment of predictive biomarkers to identify patients who will effectively respond to treatment would allow for the development of personalized therapies. As the degree of interaction of alkylating drug with DNA plays a key role in their mechanism of action, our hypothesis is that the measurement of the DNA adducts formed by alkylating drugs could be used to inform patient stratification. Beginning with busulfan, we took advantage of our DNA adductomic approach to characterize DNA adducts formed by reacting busulfan with calf-thymus DNA. Samples collected from six patients undergoing busulfan-based chemotherapy prior to allogeneic hematopoietic cell transplantation were analyzed for the presence of busulfan-derived DNA adducts. Among the 15 adducts detected in vitro, 12 were observed in the patient blood confirming the presence of a large profile of DNA adducts in vivo. Two of the detected adducts were structurally confirmed by comparison with synthetic standards and quantified in patients. These data confirm our ability to comprehensively characterize busulfan-derived DNA damage and set the stage for the development of methods to support personalized chemotherapy.

AB - DNA alkylating drugs have been used as cancer chemotherapy with variable outcomes. The establishment of predictive biomarkers to identify patients who will effectively respond to treatment would allow for the development of personalized therapies. As the degree of interaction of alkylating drug with DNA plays a key role in their mechanism of action, our hypothesis is that the measurement of the DNA adducts formed by alkylating drugs could be used to inform patient stratification. Beginning with busulfan, we took advantage of our DNA adductomic approach to characterize DNA adducts formed by reacting busulfan with calf-thymus DNA. Samples collected from six patients undergoing busulfan-based chemotherapy prior to allogeneic hematopoietic cell transplantation were analyzed for the presence of busulfan-derived DNA adducts. Among the 15 adducts detected in vitro, 12 were observed in the patient blood confirming the presence of a large profile of DNA adducts in vivo. Two of the detected adducts were structurally confirmed by comparison with synthetic standards and quantified in patients. These data confirm our ability to comprehensively characterize busulfan-derived DNA damage and set the stage for the development of methods to support personalized chemotherapy.

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ER -

Characterization and quantitation of busulfan DNA adducts in the blood of patients receiving busulfan therapy

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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