Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing

Abstract

Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samplesmore » and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. In conclusion, these initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.« less

Authors:
 [1];  [2];  [2];  [2];  [3]; ORCiD logo [4];  [5]
+ Show Author Affiliations
  1. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  3. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine; Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States); VA Northern California Health Care System, Mather, CA (United States)
  4. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine; Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
  5. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Division of Hematology and Oncology, Dept. of Internal Medicine; VA Northern California Health Care System, Mather, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1513119
Report Number(s):
LLNL-JRNL-769867
Journal ID: ISSN 0893-228X; 961209
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Research in Toxicology
Additional Journal Information:
Journal Volume: 31; Journal Issue: 10; Journal ID: ISSN 0893-228X
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Scharadin, Tiffany M., Malfatti, Michael A., Haack, Kurt, Turteltaub, Kenneth W., Pan, Chong-xian, Henderson, Paul T., and Jonas, Brian A. Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing. United States: N. p., 2018. Web. doi:10.1021/acs.chemrestox.8b00107.
Copy to clipboard
Scharadin, Tiffany M., Malfatti, Michael A., Haack, Kurt, Turteltaub, Kenneth W., Pan, Chong-xian, Henderson, Paul T., & Jonas, Brian A. Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing. United States. https://doi.org/10.1021/acs.chemrestox.8b00107
Copy to clipboard
Scharadin, Tiffany M., Malfatti, Michael A., Haack, Kurt, Turteltaub, Kenneth W., Pan, Chong-xian, Henderson, Paul T., and Jonas, Brian A. Tue . "Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing". United States. https://doi.org/10.1021/acs.chemrestox.8b00107. https://www.osti.gov/servlets/purl/1513119.
Copy to clipboard
@article{osti_1513119,
title = {Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing},
author = {Scharadin, Tiffany M. and Malfatti, Michael A. and Haack, Kurt and Turteltaub, Kenneth W. and Pan, Chong-xian and Henderson, Paul T. and Jonas, Brian A.},
abstractNote = {Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samples and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. In conclusion, these initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.},
doi = {10.1021/acs.chemrestox.8b00107},
journal = {Chemical Research in Toxicology},
number = 10,
volume = 31,
place = {United States},
year = {2018},
month = {8}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acs.chemrestox.8b00107
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 1 work
Citation information provided by
Web of Science

Figures / Tables:

Table 1 Table 1: Cell line IC50 values with 72 h continuous treatment (μM)
All figures and tables (9 total)
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML
journal, December 2017

High-dose cytosine arabinoside in the treatment of acute myeloid leukemia: Review of three randomized trials
journal, January 2006

A randomized study of high-dose cytarabine in induction in acute myeloid leukemia [see comments]
journal, March 1996

Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B
journal, December 1981

Acute Myeloid Leukemia
journal, September 1999

  • Lowenberg, Bob; Downing, James R.; Burnett, Alan
  • New England Journal of Medicine, Vol. 341, Issue 14
  • DOI: 10.1056/NEJM199909303411407

Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients
journal, January 2009

Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry
journal, April 2009

High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia
journal, September 2009

  • Löwenberg, Bob; Ossenkoppele, Gert J.; van Putten, Wim
  • New England Journal of Medicine, Vol. 361, Issue 13
  • DOI: 10.1056/NEJMoa0901409

Anthracycline Dose Intensification in Acute Myeloid Leukemia
journal, September 2009

  • Fernandez, Hugo F.; Sun, Zhuoxin; Yao, Xiaopan
  • New England Journal of Medicine, Vol. 361, Issue 13
  • DOI: 10.1056/NEJMoa0904544

Acute Myeloid Leukemia
journal, September 2015

  • Döhner, Hartmut; Weisdorf, Daniel J.; Bloomfield, Clara D.
  • New England Journal of Medicine, Vol. 373, Issue 12
  • DOI: 10.1056/NEJMra1406184

An update of current treatments for adult acute myeloid leukemia
journal, January 2016

Selecting initial treatment of acute myeloid leukaemia in older adults
journal, March 2017

Prognostic Significance of the European LeukemiaNet Standardized System for Reporting Cytogenetic and Molecular Alterations in Adults With Acute Myeloid Leukemia
journal, December 2012

  • Mrózek, Krzysztof; Marcucci, Guido; Nicolet, Deedra
  • Journal of Clinical Oncology, Vol. 30, Issue 36
  • DOI: 10.1200/JCO.2012.43.4738

Lethality of human myeloblasts correlates with the incorporation of arabinofuranosylcytosine into DNA.
journal, May 1981

  • Major, P. P.; Egan, E. M.; Beardsley, G. P.
  • Proceedings of the National Academy of Sciences, Vol. 78, Issue 5
  • DOI: 10.1073/pnas.78.5.3235

Personalized medicine for targeted and platinum-based chemotherapy of lung and bladder cancer
journal, February 2013

  • Cimino, George D.; Pan, Chong-xian; Henderson, Paul T.
  • Bioanalysis, Vol. 5, Issue 3
  • DOI: 10.4155/bio.12.325

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel
journal, January 2017

Pharmacokinetics of continuous intravenous and subcutaneous infusions of cytosine arabinoside
journal, June 1982

Effect of dose and schedule on pharmacokinetics of high-dose cytosine arabinoside in plasma and cerebrospinal fluid.
journal, September 1983

  • Slevin, M. L.; Piall, E. M.; Aherne, G. W.
  • Journal of Clinical Oncology, Vol. 1, Issue 9
  • DOI: 10.1200/JCO.1983.1.9.546

Peak plasma concentrations of doxorubicin in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma
journal, November 2001

  • Hempel, Georg; Flege, Silke; Würthwein, Gudrun
  • Cancer Chemotherapy and Pharmacology, Vol. 49, Issue 2
  • DOI: 10.1007/s00280-001-0392-4

Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass
journal, November 2010

  • Barpe, Deise Raquel; Rosa, Daniela Dornelles; Froehlich, Pedro Eduardo
  • European Journal of Pharmaceutical Sciences, Vol. 41, Issue 3-4
  • DOI: 10.1016/j.ejps.2010.07.015

Detection of Adriamycin-DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations
journal, August 2008

  • Coldwell, K. E.; Cutts, S. M.; Ognibene, T. J.
  • Nucleic Acids Research, Vol. 36, Issue 16
  • DOI: 10.1093/nar/gkn439

In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia: Resistance to Cytarabine in AML
journal, June 2002

Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II
journal, October 1984

New Mechanistic and Functional Insights into DNA Topoisomerases
journal, June 2013

DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis
journal, May 2013

Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death
journal, May 2006

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice
journal, November 2016

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer: Diagnostic microdosing approach
journal, May 2017

  • Wang, Si-Si; Zimmermann, Maike; Zhang, Hongyong
  • International Journal of Cancer, Vol. 141, Issue 3
  • DOI: 10.1002/ijc.30747

The Power and Potential of Doxorubicin-DNA Adducts
journal, February 2005

  • Cutts, Suzanne; Nudelman, Abraham; Rephaeli, Ada
  • IUBMB Life (International Union of Biochemistry and Molecular Biology: Life), Vol. 57, Issue 2
  • DOI: 10.1080/15216540500079093

Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia
journal, September 2013

Quantitative scoring of differential drug sensitivity for individually optimized anticancer therapies
journal, June 2014

  • Yadav, Bhagwan; Pemovska, Tea; Szwajda, Agnieszka
  • Scientific Reports, Vol. 4, Issue 1
  • DOI: 10.1038/srep05193

Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study
journal, January 2018

    Sort by:
    [ × clear filter / sort ]

    Works referencing / citing this record:

    Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science
    journal, May 2019

    • Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A.
    • Toxics, Vol. 7, Issue 2
    • DOI: 10.3390/toxics7020027
      Sort by:
      [ × clear filter / sort ]

      Figures / Tables found in this record:

      Table 1 (p. 27)table
      Figure 1 (p. 30)figure
      Figure 2 (p. 31)figure
      Figure 3 (p. 32)figure
      Figure 4 (p. 33)figure
      Figure 5 (p. 33)figure
      Figure S1 (p. 37)figure
      Figure S2 (p. 38)figure
      Figure S3 (p. 38)figure
        [ × clear filter / sort ]
        Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.

        Similar Records in DOE PAGES and OSTI.GOV collections: