Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors.

BACKGROUND: Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS: This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTS: At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS: Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.

Reliability and validity of the Tobacco Craving Questionnaire and validation of a craving-induction procedure using multiple measures of craving and mood.

AIMS: To determine the reliability and validity of the Tobacco Craving Questionnaire (TCQ) and the validity of imagery scripts to elicit self-reported tobacco craving. DESIGN: Active imagery of three auditory scripts that described no-, low- and high-intensity of smoking urge. PARTICIPANTS: Current cigarette smokers (24 men, 24 women) not attempting to quit or reduce smoking. MEASUREMENTS: After each imagery condition, participants completed the 47-item TCQ, a Mood Form and Visual Analog Scale (VAS) questions. FINDINGS: Reliability of measures was demonstrated by internal consistency and unidimensionality of the four TCQ factors across imagery conditions. Criterion-related validity was demonstrated by an orderly increase in scores on the TCQ and VAS craving measures as a function of craving intensity of the imagery scripts. Increases in effect size parameters and parallel decreases in the stability of test-retest reliability for all craving measures indicated the validity of the imagery procedure. Convergent and discriminant validity were established by the craving scripts increasing self-reported craving, the no-craving (positive-affect) script increasing positive mood, the no-craving script not affecting craving and the craving scripts not affecting positive mood. CONCLUSIONS: Findings further demonstrated the reliability and validity of the TCQ as a multi-factorial instrument to assess the construct of tobacco craving and suggested that the lability of craving, rather than inconsistency and instability in its measurement, was responsible for observed effects.