Development of a CART Model to Predict the Synthesis of Cardiotoxic Daunorubicinol in Heart Tissue Samples From Donors With and Without Down Syndrome.
Daunorubicin (DAUN) and doxorubicin (DOX) are used to treat a variety of cancers. The use of DAUN and DOX is hampered by the development of cardiotoxicity. Clinical evidence suggests that patients with leukemia and Down syndrome are at increased risk for anthracycline-related cardiotoxicity. Carbonyl reductases and aldo-keto reductases (AKRs) catalyze the reduction of DAUN and DOX into cardiotoxic C-13 alcohol metabolites. Anthracyclines also exert cardiotoxicity by triggering mitochondrial dysfunction. In recent studies, a collection of heart samples from donors with and without Down syndrome was used to investigate determinants for anthracycline-related cardiotoxicity including cardiac daunorubicin reductase activity (DA), carbonyl reductase/AKRs protein expression, mitochondrial DNA content (mtDNA), and AKR7A2 DNA methylation status. In this study, the available demographic, biochemical, genetic, and epigenetic data were integrated through classification and regression trees analysis with the aim of pinpointing the most relevant variables for the synthesis of cardiotoxic daunorubicinol (i.e., DA). Seventeen variables were considered as potential predictors. Leave-one-out-cross-validation was performed for model selection and to estimate the generalization error. The classification and regression trees analysis model and variable importance measures suggest that cardiac mtDNA content, mtDNA(4977) deletion frequency, and AKR7A2 protein content are the most important variables in determining DA.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York 14260.
Carrie C
CC
Hoefer
Department of Biostatistics, School of Public Health and Health Professions, The State University of New York at Buffalo, Buffalo, New York 14260.
Rachael Hageman
RH
Blair
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York 14260. Electronic address: jgblanco@buffalo.edu.
Javier G
JG
Blanco
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000378:metabolism*; D054715:Cardiotoxins / Q000009:adverse effects / Q000378:metabolism*; D002648:Child; D003663:Decision Trees; D004314:Down Syndrome / Q000188:drug therapy / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects / Q000378:metabolism*; D005544:Forecasting; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D055815:Young Adult
D000903:Antibiotics, Antineoplastic; D054715:Cardiotoxins; D004317:Doxorubicin
anthracyclines; classification and regression trees; heart