Preclinical evaluation of pemetrexed in pediatric solid tumors

Norris, Robin E.; Rappaport, Eric; Adamson, Peter C.

doi:10.1002/pbc.23286

Cited by 2 publications

(3 citation statements)

References 14 publications

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“…Drugs, drug combinations, or vehicle control were added to achieve final concentrations: olaparib (0.02–100 µM), irinotecan (0.0005–100 µM), SN38 (4 × 10 −5 –0.2 µM), melphalan (0.06–200 µM), doxorubicin (0.0003–0.6 µM), carboplatin (0.02–200 µM), VCR (2 × 10 −5 –0.1 µM). Growth inhibition was assessed using the SRB assay as previously described . The 50% growth inhibitory concentration (IC 50 ) was determined by fitting a 4 parameter logistic equation to the data:

% survival = [\frac{({normalE}_{\max} - {normalE}_{\min})}{{(1 + dose / E {normalC}_{50})}^{slope}}] + {normalE}_{\min}

where E max and E min are the concentrations at which maximum and minimum cytotoxicity are observed, respectively, and EC 50 is the concentration at which 50% of the maximum cytotoxicity is attained (E min + E max )/2.…”

Section: Methodsmentioning

confidence: 99%

“…Drugs, drug combinations, or vehicle control were added to achieve final concentrations: olaparib (0.02-100 mM), irinotecan (0.0005-100 mM), SN38 (4 Â 10 À5 -0.2 mM), melphalan (0.06-200 mM), doxorubicin (0.0003-0.6 mM), carboplatin (0.02-200 mM), VCR (2 Â 10 À5 -0.1 mM). Growth inhibition was assessed using the SRB assay as previously described [37,38]. The 50% growth inhibitory concentration (IC 50 ) was determined by fitting a 4 parameter logistic equation to the data:…”

Section: In Vitro Growth Inhibition Assaymentioning

confidence: 99%

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Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors

Norris

Adamson

Nguyen

et al. 2013

Pediatric Blood & Cancer

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Background Poly(ADP-ribose) polymerase (PARP) signals DNA damage and facilitates DNA repair. PARP inhibitors are being evaluated in cancers with defective DNA repair mechanisms or in combination with cytotoxic therapy or radiation. We evaluated the PARP inhibitor, olaparib, in combination with chemotherapy using in vitro and in vivo pediatric solid tumor models. Procedure The IC50 of olaparib alone and in combination with cytotoxic agents was determined in 10 pediatric solid tumor cell lines. Synergy was assessed using the combination index of Chou-Talalay. Olaparib alone and in combination with topotecan/cyclophosphamide was evaluated in xenograft models of Ewing sarcoma (ES) and neuroblastoma (NGP). PAR activity was evaluated in cell lines and tumor lysates. Results Olaparib induced growth inhibition, median (range) IC50=3.6 (1–33.8) µM, and inhibited PAR activity in pediatric solid tumor cell lines. The addition of olaparib to DNA damaging agents resulted in additive to synergistic interactions. In ES and NGP xenografts, olaparib inhibited PAR activity by 88% to 100% as a single agent and 100% when administered with cyclophosphamide/topotecan. Although the addition of olaparib did not antagonize the activity of cyclophosphamide/topotecan, clear evidence of synergy could not be demonstrated. Conclusions In pediatric solid tumor cell lines, clinically achievable concentrations of single agent olaparib caused growth inhibition. Although the in vitro data demonstrated synergistic efficacy of olaparib when added to the camptothecins and alkylating agents, synergy was not discernible in vivo. Clinical trials of PARP inhibitors in combination DNA damaging agents are necessary to establish the role of PARP inhibitors in childhood cancer.

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% survival = [\frac{({normalE}_{\max} - {normalE}_{\min})}{{(1 + dose / E {normalC}_{50})}^{slope}}] + {normalE}_{\min}

Section: Methodsmentioning

confidence: 99%

Section: In Vitro Growth Inhibition Assaymentioning

confidence: 99%

Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors

Norris

Adamson

Nguyen

et al. 2013

Pediatric Blood & Cancer

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“…A previous report showed that pemetrexed, a newly developed anti-folate chemotherapy drug, could effectively inhibit the growth of some ES cells at a low dose (Mean IC 50 = 64 (39, 89) nM), but its mechanisms are still unknown. 19 Then, we chose RD-ES cells, which had been used to observe the effect of pemetrexed in this report, for the following studies. The results showed that pemetrexed treatment not only dose-dependently decreased the expression of miR-146b-5p ( p < 0.01, Figure 6(a) ) but also significantly inhibited the proliferation of RD-ES cells ( p < 0.01, Figure 6(b) ).…”

Section: Resultsmentioning

confidence: 99%

The miR-146b-5p promotes Ewing’s sarcoma cells progression via suppressing the expression of BTG2

Zhang

et al. 2021

Science Progress

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Ewing sarcoma (ES) is a malignant tumor that occurs mostly in children. However, the underlying mechanisms of ES are still unknown. Analyzing the results of two previous miRNA array reports, we found that miR-146b-5p might be an onco-miRNA in ES progression. To test this hypothesis, we detected the expression levels of miR-146b-5p by real-time PCR and observed the effects of miR-146b-5p on the progression of ES cells by CCK8 and transwell assays. Bioinformatics and luciferase assays were used to identify the target genes of miR-146b-5p. It showed that the expression levels of miR-146b-5p were upregulated in ES cell lines compared with human mesenchymal stem cells (MSCs). Up- or downregulation of miR-146b-5p in ES cell lines could effectively promote or block the proliferation, migration, and invasion of ES cells, respectively. Furthermore, we demonstrated that BTG2 was one of the target genes and mediated the effects of miR-146b-5p in ES cells. Interestingly, we also found that miR-146b-5p was partly involved in the anticancer effects of pemetrexed in ES cells. Our study revealed that miR-146b-5p affected the progression of ES by suppressing BTG2, which might shed light on anticancer drug development and ES treatment in the future.

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Preclinical evaluation of pemetrexed in pediatric solid tumors

Cited by 2 publications

References 14 publications

Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors

Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors

The miR-146b-5p promotes Ewing’s sarcoma cells progression via suppressing the expression of BTG2

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