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Lipopolysaccharide-Induced CXCL10 mRNA Level and Six Stimulant-mRNA Combinations in Whole Blood: Novel Biomarkers for Bortezomib Responses Obtained from a Prospective Multicenter Trial for Patients with Multiple Myeloma.

Watanabe T, Mitsuhashi M, Sagawa M, Ri M, Suzuki K, Abe M, Ohmachi K, Nakagawa Y, Nakamura S, Chosa M, Iida S, Kizaki M - PLoS ONE (2015)

Bottom Line: Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests.Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose.Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients.

View Article: PubMed Central - PubMed

Affiliation: Hematology Division, National Cancer Center Hospital, Tokyo, Japan.

ABSTRACT
To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients.

No MeSH data available.


Related in: MedlinePlus

Bortezomib-induced inhibition of LPS-induced CXCL10 mRNA ex vivo.Peripheral blood obtained from 3 healthy volunteers was pre-treated with various concentrations of bortezomib for 1 h and then further stimulated with LPS or PBS (as the control) for an additional 4 h. The fold increase in (A) ACTB and (B) CXCL10 expression is shown. Each symbol represents a single individual.
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pone.0128662.g003: Bortezomib-induced inhibition of LPS-induced CXCL10 mRNA ex vivo.Peripheral blood obtained from 3 healthy volunteers was pre-treated with various concentrations of bortezomib for 1 h and then further stimulated with LPS or PBS (as the control) for an additional 4 h. The fold increase in (A) ACTB and (B) CXCL10 expression is shown. Each symbol represents a single individual.

Mentions: This observation was likely not explained by the immunological activity of CXCL10, as CXCL10 is also expressed in human myeloma cell lines [45] and is known to stimulate myeloma cell migration [46] and adhesion to bone marrow stromal cells [47]. Thus, MM cells may be more susceptible to the bortezomib-induced inhibition of CXCL10 mRNA expression than immune cells. Moreover, when bortezomib was added to whole blood prior to LPS stimulation ex vivo, CXCL10 mRNA induction was inhibited in a dose-dependent manner (Fig 3). Thus, LPS-induced CXCL10 expression in ex vivo blood samples could serve as a surrogate marker for the effect of bortezomib in vivo.


Lipopolysaccharide-Induced CXCL10 mRNA Level and Six Stimulant-mRNA Combinations in Whole Blood: Novel Biomarkers for Bortezomib Responses Obtained from a Prospective Multicenter Trial for Patients with Multiple Myeloma.

Watanabe T, Mitsuhashi M, Sagawa M, Ri M, Suzuki K, Abe M, Ohmachi K, Nakagawa Y, Nakamura S, Chosa M, Iida S, Kizaki M - PLoS ONE (2015)

Bortezomib-induced inhibition of LPS-induced CXCL10 mRNA ex vivo.Peripheral blood obtained from 3 healthy volunteers was pre-treated with various concentrations of bortezomib for 1 h and then further stimulated with LPS or PBS (as the control) for an additional 4 h. The fold increase in (A) ACTB and (B) CXCL10 expression is shown. Each symbol represents a single individual.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482752&req=5

pone.0128662.g003: Bortezomib-induced inhibition of LPS-induced CXCL10 mRNA ex vivo.Peripheral blood obtained from 3 healthy volunteers was pre-treated with various concentrations of bortezomib for 1 h and then further stimulated with LPS or PBS (as the control) for an additional 4 h. The fold increase in (A) ACTB and (B) CXCL10 expression is shown. Each symbol represents a single individual.
Mentions: This observation was likely not explained by the immunological activity of CXCL10, as CXCL10 is also expressed in human myeloma cell lines [45] and is known to stimulate myeloma cell migration [46] and adhesion to bone marrow stromal cells [47]. Thus, MM cells may be more susceptible to the bortezomib-induced inhibition of CXCL10 mRNA expression than immune cells. Moreover, when bortezomib was added to whole blood prior to LPS stimulation ex vivo, CXCL10 mRNA induction was inhibited in a dose-dependent manner (Fig 3). Thus, LPS-induced CXCL10 expression in ex vivo blood samples could serve as a surrogate marker for the effect of bortezomib in vivo.

Bottom Line: Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests.Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose.Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients.

View Article: PubMed Central - PubMed

Affiliation: Hematology Division, National Cancer Center Hospital, Tokyo, Japan.

ABSTRACT
To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients.

No MeSH data available.


Related in: MedlinePlus