Lack of association of CYP2B6 pharmacogenetics with cyclophosphamide toxicity in patients with cancer

Hwang, Mary; Medley, Sarah; Shakeel, Faisal; Vanderwerff, Brett; Zawistowski, Matthew; Kidwell, Kelley M.; Hertz, Daniel L

doi:10.1007/s00520-022-07118-y

Cited by 3 publications

(4 citation statements)

References 34 publications

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“…Our results were in line with the findings in Japanese breast cancer patients receiving a standard AC regimen (doxorubicin and cyclophosphamide) that grade 4 neutropenia hardly developed in CYP2B6*6 carriers 55 . However, other studies found no association of hematologic toxicity with pharmacokinetics of cyclophosphamide and its metabolites or with CYP2B6 polymorphisms 19 , 34 , 53 , 57 . Increased hydroxylation activity forming 4-hydroxycyclophosphamide was linked to a significant reduction of neutrophils and platelets and to low hemoglobin concentrations in pediatric patients with brain tumours that also confirmed the association between high bioactivation rate and increased risk of hematologic toxicity 34 .…”

Section: Discussionmentioning

confidence: 91%

“…The g.-82T>C (rs34223104) single nucleotide variation (SNV) in CYP2B6*22 allele appears to enhance the transcription of CYP2B6 gene leading to increased mRNA expression and catalytic activity, and carriers of CYP2B6*22 are categorized as ’rapid/ultra-rapid’ metabolizers 42 , 49 – 51 . Several CYP2B6 alleles have been clearly demonstrated to result in decreased or increased CYP2B6 activity; however, the association between CYP2B6 genetic polymorphisms and cyclophosphamide pharmacokinetics or clinical outcomes of cyclophosphamide therapy is often controversial 34 , 44 , 52 – 57 . The CYP2B6 genotype–phenotype mismatch is partly explained by non-genetic factors, such as co-medications, sex and age, which can mask the effect of CYP2B6 allelic variants.…”

Section: Introductionmentioning

confidence: 99%

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Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma

Mangó

Fekete

Kiss

et al. 2023

Sci Rep

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Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients’ CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients’ age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma

Mangó

Fekete

Kiss

et al. 2023

Sci Rep

View full text Add to dashboard Cite

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“…On the other hand, other studies have concluded that CYP polymorphisms (including CYP2B6) do not play a significant role in the response variation to Cy with respect to complete remission, while clinical factors such as patients' ages and cancer grades may be more significant [ 54 – 56 , 105 – 109 ]. Recently, a lack of association of CYP2B6 pharmacogenetics with Cy toxicity in patients was reported; moreover, aldehyde dehydrogenases 1A1 (ALDH1A1) rs8187996 may have a lower risk of Cy toxicity compared to wild-type patients [ 110 ]. In pediatric patients with non-Hodgkin's B-cell lymphomas, the CYP2B6 genotype was reported to influence Cy but had no clear impact on the clinical outcome [ 111 ].…”

Section: Cyclophosphamide Metabolismmentioning

confidence: 99%

Cyclophosphamide Pharmacogenomic Variation in Cancer Treatment and Its Effect on Bioactivation and Pharmacokinetics

El-Serafi,

Steele

2024

Advances in Pharmacological and Pharmaceutical Sciences

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Cyclophosphamide (Cy) is a prodrug that is mainly bioactivated by cytochrome P450 (CYP) 2B6 enzyme. Several other enzymes are also involved in its bioactivation and affect its kinetics. Previous studies have shown the effect of the enzymes’ genetic polymorphisms on Cy kinetics and its clinical outcome. These results were controversial primarily because of the involvement of several interacting enzymes in the Cy metabolic pathway, which can also be affected by several clinical factors as well as other drug interactions. In this review article, we present the effect of CYP2B6 polymorphisms on Cy kinetics since it is the main bioactivating enzyme, as well as discussing all previously reported enzymes and clinical factors that can alter Cy efficacy. Additionally, we present explanations for key Cy side effects related to the nature and site of its bioactivation. Finally, we discuss the role of busulphan in conditioning regimens in the Cy metabolic pathway as a clinical example of drug‐drug interactions involving several enzymes. By the end of this article, our aim is to have provided a comprehensive summary of Cy pharmacogenomics and the effect on its kinetics. The utility of these findings in the development of new strategies for Cy personalized patient dose adjustment will aid in the future optimization of patient specific Cy dosages and ultimately in improving clinical outcomes. In conclusion, CYP2B6 and several other enzyme polymorphisms can alter Cy kinetics and consequently the clinical outcomes. However, the precise quantification of Cy kinetics in any individual patient is complex as it is clearly under multifactorial genetic control. Additionally, other clinical factors such as the patient’s age, diagnosis, concomitant medications, and clinical status should also be considered.

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“…One of the key target organs for researching drug toxicity is the kidney. Due to the activation of polymorphic metabolic enzymes, CTX is a chemotherapy medication routinely used in clinics with significant adverse effects [ 1 , 2 ]. Approximately 30% of this substance is excreted in the urine in an activated state, causing severe nephrotoxicity and urinary system side effects in cystic fibrosis, as well as producing related inflammatory markers [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Optimization of the Flavonoid Extraction Process from the Stem and Leaves of Epimedium Brevicornum and Its Effects on Cyclophosphamide-Induced Renal Injury

Shi,

Pei,

Sun

et al. 2023

Molecules

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Cyclophosphamide (CTX) is a broad-spectrum alkylated antitumor drug. It is clinically used in the treatment of a variety of cancers, and renal toxicity is one of the adverse reactions after long-term or repeated use, which not only limits the therapeutic effect of CTX, but also increases the probability of kidney lesions. The total flavonoids of Epimedium stem and leaf (EBF) and Icariin (ICA) are the main medicinal components of Epimedium, and ICA is one of the main active substances in EBF. Modern pharmacological studies have shown that EBF has a variety of biological activities such as improving osteoporosis, promoting cell proliferation, antioxidant and anti-inflammatory properties, etc. However, few studies have been conducted on the nephrotoxicity caused by optimized CTX extraction, and protein-ligand binding has not been involved. This research, through the response surface optimization extraction of EBF, obtained the best extraction conditions: ethanol concentration was 60%, solid-liquid ratio of 25:1, ultrasonic time was about 25 min. Combined with mass spectrometry (MS) analysis, EBF contained ICA, ichopidin A, ichopidin B, ichopidin C, and other components. In this study, we adopted a computational chemistry method called molecular docking, and the results show that Icariin was well bound to the antioxidant target proteins KEAP1 and NRF2, and the anti-inflammatory target proteins COX-2 and NF-κB, with free binding energies of −9.8 kcal/mol, −11.0 kcal/mol, −10.0 kcal/mol, and −8.1 kcal/mol, respectively. To study the protective effect of EBF on the nephrotoxicity of CTX, 40 male Kunming mice (weight 18 ± 22) were injected with CTX (80 mg/kg) for 7 days to establish the nephrotoxicity model and were treated with EBF (50 mg/kg, 100 mg/kg) for 8 days by gavage. After CTX administration, MDA, BUN, Cre, and IL-6 levels in serum increased, MDA increased in kidney, GPT/ALT and IL-6 increased in liver, and IL-6 increased in spleen and was significant ((p < 0.05 or (p < 0.01)). Histopathological observation showed that renal cortex glomerular atrophy necrosis, medullary inflammatory cell infiltration, and other lesions. After administration of EBF, CTX-induced increase in serum level of related indexes was reduced, and MDA in kidney, GPT/ALT and IL-6 in liver, and IL-6 in spleen were increased. At the same time, histopathological findings showed that the necrosis of medullary and corticorenal tubular epithelium was relieved at EBF (50 mg/kg) dose compared with the CTX group, and the glomerular tubular necrosis gradually became normal at EBF (100 mg/kg) dose. Western blot analysis of Keap1 and Nrf2 protein expression in kidney tissue showed that compared with model CTX group, the drug administration group could alleviate the high expression of Keap1 protein and low expression of Nrf2 protein in kidney tissue. Conclusion: After the optimal extraction of total flavonoids from the stems and leaves of Epimedium, the molecular docking technique combined with animal experiments suggested that the effective component of the total flavonoids of Epimedium might activate the Keap1-Nrf2 signaling pathway after treatment to reduce the inflammation and oxidative stress of kidney tissue, so as to reduce kidney damage and improve kidney function. Therefore, EBF may become a new natural protective agent for CTX chemotherapy in the future.

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Lack of association of CYP2B6 pharmacogenetics with cyclophosphamide toxicity in patients with cancer

Cited by 3 publications

References 34 publications

Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma

Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma

Cyclophosphamide Pharmacogenomic Variation in Cancer Treatment and Its Effect on Bioactivation and Pharmacokinetics

Optimization of the Flavonoid Extraction Process from the Stem and Leaves of Epimedium Brevicornum and Its Effects on Cyclophosphamide-Induced Renal Injury

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