Cyclophosphamide metabolite inducing apoptosis in RLS mouse lymphosarcoma cells is a substrate for P-glycoprotein

Patutina, Olga; Миронова, Н. Л.; Logashenko, Evgeniya B.; Попова, Н. А.; Николин, В. П.; Vasil’ev, G. V.; Каледин, В. И.; Zenkova, Marina A.; Власов, В. В.

doi:10.1007/s10517-012-1525-y

Cited by 7 publications

(4 citation statements)

References 12 publications

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“…In an ATP‐dependent manner, ATP‐binding cassette (ABC) transporters extrude drugs, metabolites, and other compounds from cells. ABC‐transporter B1 (ABCB1) (CD243) has specificity for various substrates, among them cytotoxic agents such as cyclophosphamide (CPA) . ABCB1 can be specifically blocked in vitro, and is inhibited by some commonly used drugs (e.g.…”

Section: Introductionmentioning

confidence: 99%

Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

et al. 2014

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Section: Introductionmentioning

confidence: 99%

Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

et al. 2014

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“…Seven of the 16 drugs were underestimated. Among the seven drugs, digoxin and riboflavin had transporter‐mediated oral absorption ; zidovudine had a strong first‐pass effect; amiloride and cyclophosphamide were inhibitors of organic cation/carnitine transporter 1 and multidrug resistance protein 1, respectively. The pK a of pyrazinamide is −0.5 , and different pH values along the gastrointestinal tract might affect its permeability.…”

Section: Resultsmentioning

confidence: 99%

Structure‐based prediction of human intestinal membrane permeability for rapid in silico BCS classification

Sun¹,

Liu²,

Xiang³

et al. 2013

Biopharm & Drug Disp

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Human effective intestinal membrane permeability (Peff) is one of the two important indicators for drug classification according to the Biopharmaceutical Classification System (BCS), and contributes greatly to the performance of oral drug absorption. Here, a structure-based in silico predictive model of Peff was developed successfully to facilitate in silico BCS classification in the early stage of drug discovery, even before the compound was synthesized. The quantitative structure-Peff relationship for 30 drugs was constructed based on seven structural parameters. Then the model was built by the multiple linear regression method and internally validated by the residual analysis, the normal probability-probability plot and the Williams plot. For the entire data set, the R² and adjusted R² values were 0.782 and 0.712, respectively. The results indicated that the fitted model was robust, stable and satisfied all the prerequisites of the regression models. As for the 102 tested drugs, the predicted Peff values had a good correlation with the experimental human absorbed fraction (Fa). This model was also used to perform high/low Peff classification for 57 drugs that have been classified according to the BCS, and 72% of drugs could be classified correctly, indicating that the developed model can be used for rapid BCS classification in the early stages of drug discovery.

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“…Thus, we were also able to correlate expression with the specific type of chemotherapy that the patients received. Notably, 3 out of the 5 chemotherapy drugs methotrexate 37 , vincristine 37 and cyclophosphamide 38 used to treat this cohort are ABCB1 substrates. In the primary chemotherapy-led trial cohort, ABCB1 positivity was an independent prognostic factor for EFS, with ABCB1-positive patients having significantly shorter mean EFS of just 2.7 years compared to their ABCB1 negative counterparts who took a mean of 8.6 years to experience an event.…”

Section: Discussionmentioning

confidence: 99%

A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma

Sabnis

Storer

Liu

et al. 2019

Sci Rep

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Three of the hallmarks of poor prognosis in paediatric ependymoma are drug resistance, local invasion and recurrence. We hypothesised that these hallmarks were due to the presence of a sub-population of cancer stem cells expressing the multi-drug efflux transporter ABCB1. ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p ≤ 0.05–0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p ≤ 0.001) and invasion (p ≤ 0.001). We demonstrate that ABCB1 positive patients from an infant chemotherapy-led trial (CNS9204) had a shorter mean event free survival (EFS) (2.7 versus 8.6 years; p = 0.007 log-rank analysis) and overall survival (OS) (5.4 versus 12 years; p = 0.009 log-rank analysis). ABCB1 positivity also correlated with reduced event free survival in patients with incompletely resected tumours who received chemotherapy across CNS9204 and CNS9904 (a radiotherapy-led SIOP 1999-04 trial cohort; p = 0.03). ABCB1 is a predictive marker of chemotherapy response in ependymoma patients and vardenafil, currently used to treat paediatric pulmonary hypertension in children, could be repurposed to reduce chemoresistance, migration and invasion in paediatric ependymoma patients at non-toxic concentrations.

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Cyclophosphamide metabolite inducing apoptosis in RLS mouse lymphosarcoma cells is a substrate for P-glycoprotein

Cited by 7 publications

References 12 publications

Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

Structure‐based prediction of human intestinal membrane permeability for rapid in silico BCS classification

A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma

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