Obesity-related genomic instability and altered xenobiotic metabolism: possible consequences for cancer risk and chemotherapy

Bankoglu, Ezgi Eyluel; Stopper, Helga

doi:10.1017/erm.2022.22

Cited by 6 publications

(5 citation statements)

References 87 publications

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“…Although the comet assay, after an analysis of a huge registry/database of more than 19,000 individuals, has established certain values for healthy, cancer-free, cancer-prone, and deceased populations (the ones that will be in the mortality registry) [ 18 , 19 ], the micronucleus cytome assay has not been fully explored with all its parameters, usually only for MN frequency [ 21 , 25 , 27 , 60 ]. As can be seen in the mentioned reviews, although both assays demonstrated a positive connection between elevated MN frequency and comet assay parameters and obesity, studies and results are still scarce, with very little data on the severely obese without studies using both assays on the severely obese in those reviews [ 21 , 25 , 27 , 60 ]. Considering that NBs are a biomarker of gene amplification, NPBs are a biomarker of di-centric chromosomes and can demonstrate different types of DNA damage in comparison to the MN assay, which is a biomarker of whole/or partial chromosome loss.…”

Section: Discussionmentioning

confidence: 99%

Combined Approach: FFQ, DII, Anthropometric, Biochemical and DNA Damage Parameters in Obese with BMI ≥ 35 kg m−2

et al. 2023

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Although obesity with its comorbidities is linked with higher cancer risk, the data on genome stability in the obese/severely obese are scarce. This is the first study with three DNA damage assessment assays (Fpg-modified and alkaline comet assays and micronucleus cytome assay) performed on a severely obese population (n = 53) where the results were compared with daily intake of food groups, nutrient intake, dietary inflammatory index (DII), and anthropometric and biochemical parameters usually measured in obese individuals. Results demonstrated the association between DNA damage levels and a decrease in cell proliferation with anthropometric measurements and the severity of obese status, together with elevated levels of urates, inorganic phosphates, chlorides, and hs troponin I levels. DII was connected with oxidative DNA damage, while BMI and basal metabolic rate (BMR) were associated with a decrease in cell proliferation and DNA damage creation. Measured daily BMR and calculated daily energy intake from the food frequency questionnaire (FFQ) demonstrated no significant difference (1792.80 vs. 1869.86 kcal day−1 mean values). Groups with higher DNA damage than expected (tail intensity in comet assay >9% and >12.4%, micronucleus frequency >13), consumed daily, weekly, and monthly more often some type of food groups, but differences did not show a clear influence on the elevated DNA damage levels. Combination of all three DNA damage assays demonstrated that some type of damage can start earlier in the obese individual lifespan, such as nuclear buds and nucleoplasmic bridges, then comes decrease in cell proliferation and then elevated micronucleus frequencies, and that primary DNA damage is not maybe crucial in the overweight, but in severely obese. Biochemically changed parameters pointed out that obesity can have an impact on changes in blood cell counts and division and also on genomic instability. Assays were able to demonstrate groups of sensitive individuals that should be further monitored for genomic instability and cancer prevention, especially when obesity is already connected with comorbidities, 13 different cancers, and a higher mortality risk with 7–10 disease-free years loss. In the future, both DNA damage and biochemical parameters should be combined with anthropometric ones for further obese monitoring, better insight into biological changes in the severely obese, and a more individual approach in therapy and treatment. Patients should also get a proper education about the foodstuff with pro- and anti-inflammatory effect.

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Section: Discussionmentioning

confidence: 99%

Combined Approach: FFQ, DII, Anthropometric, Biochemical and DNA Damage Parameters in Obese with BMI ≥ 35 kg m−2

et al. 2023

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“…Furthermore, obesity can affect the expression of hepatic and intestinal drug transporters, which can affect drug uptake and excretion 64 . Obesity can alter the activity and expression of several Phase I (oxidation, reduction, hydrolysis) cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP2E1 68 . Although the results of the effect of obesity on hepatic drug metabolizing enzymes vary, overall obesity decreases the activity of CYP2C19, 69 while increasing the activity of CYP2C9, CYP2C92E1, and CYP2C93A4 68 .…”

Section: Effect Of Obesity On Small‐molecule Anticancer Drugsmentioning

confidence: 99%

“…Obesity can alter the activity and expression of several Phase I (oxidation, reduction, hydrolysis) cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP2E1 68 . Although the results of the effect of obesity on hepatic drug metabolizing enzymes vary, overall obesity decreases the activity of CYP2C19, 69 while increasing the activity of CYP2C9, CYP2C92E1, and CYP2C93A4 68 . Obesity is also associated with enhanced capacity for Phase II hepatic drug metabolism including N ‐acetylation, sulfation, and glucuronidation 70,71 …”

Section: Effect Of Obesity On Small‐molecule Anticancer Drugsmentioning

confidence: 99%

“…68 Although the results of the effect of obesity on hepatic drug metabolizing enzymes vary, overall obesity decreases the activity of CYP2C19, 69 while increasing the activity of CYP2C9, CYP2C92E1, and CYP2C93A4. 68 Obesity is also associated with enhanced capacity for Phase II hepatic drug metabolism including Nacetylation, sulfation, and glucuronidation. 70,71 Clearance and excretion of drugs and metabolites from the body are closely governed by the liver and kidney.…”

Section: S90mentioning

confidence: 99%

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Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents

Zamboni,

Charlab,

Burckart

et al. 2023

The Journal of Clinical Pharma

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An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small‐molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier‐mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.

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“…Interestingly enough, increased adiposity appears to hamper cancer cell response to chemotherapy by reducing fatty acid oxidation involved in DNA damage repair, ultimately decreasing cell death. This is not unexpected given the fact that adiposity would be expected to affect various aspects of drug metabolism, and therefore could influence drug distribution, treatment response, and adverse effects [8]. Additionally, obesity is associated with an increased risk of complications during surgery and radiation therapy [9].…”

mentioning

confidence: 99%

Editorial: unravelling the trifecta: obesity, cancer, and DNA damage

Kalea,

Klimis-Zacas

2024

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Obesity-related genomic instability and altered xenobiotic metabolism: possible consequences for cancer risk and chemotherapy

Cited by 6 publications

References 87 publications

Combined Approach: FFQ, DII, Anthropometric, Biochemical and DNA Damage Parameters in Obese with BMI ≥ 35 kg m−2

Combined Approach: FFQ, DII, Anthropometric, Biochemical and DNA Damage Parameters in Obese with BMI ≥ 35 kg m−2

Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents

Editorial: unravelling the trifecta: obesity, cancer, and DNA damage

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