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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

Ex vivo mRNA induction in blood obtained prior to bortezomib treatment.The fold increase in (A) LPS-induced GMCSF, (B) ZA-induced GMCSF, (C) LPS-induced CXCL10 (top panel), (D) PHA-induced CCL4, (E) LPS-induced CCL4 and (F) ZA-induced CCL4 (lower panel) mRNA in the CR, VGPR, PR, SD and PD groups is shown. The statistically significant difference between the CR+VGPR and SD+PD groups is shown. t: Student’s t-test, M: Mann-Whitney test. Dotted line: fold increase = 3. Samples showing a fold increase in ACTB (which was > 3) were removed from the analysis. Horizontal bars: the mean values.
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pone.0128662.g001: Ex vivo mRNA induction in blood obtained prior to bortezomib treatment.The fold increase in (A) LPS-induced GMCSF, (B) ZA-induced GMCSF, (C) LPS-induced CXCL10 (top panel), (D) PHA-induced CCL4, (E) LPS-induced CCL4 and (F) ZA-induced CCL4 (lower panel) mRNA in the CR, VGPR, PR, SD and PD groups is shown. The statistically significant difference between the CR+VGPR and SD+PD groups is shown. t: Student’s t-test, M: Mann-Whitney test. Dotted line: fold increase = 3. Samples showing a fold increase in ACTB (which was > 3) were removed from the analysis. Horizontal bars: the mean values.

Mentions: The fold increase in LPS-induced GMCSF, CXCL10 and CCL4, PHA-induced CCL4 and ZA-induced GMCSF and CCL4 were significantly higher in the CR and VGPR groups than in the SD and PD groups, as determined by both parametric t-tests and non-parametric Mann-Whitney tests, whereas the PR group exhibited an intermediate value (Fig 1). Moreover, 100, 67, 56, 42 and 0% of patients showed more than 3-fold increases in LPS-induced CXCL10 (dotted line in Fig 1).


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)

Ex vivo mRNA induction in blood obtained prior to bortezomib treatment.The fold increase in (A) LPS-induced GMCSF, (B) ZA-induced GMCSF, (C) LPS-induced CXCL10 (top panel), (D) PHA-induced CCL4, (E) LPS-induced CCL4 and (F) ZA-induced CCL4 (lower panel) mRNA in the CR, VGPR, PR, SD and PD groups is shown. The statistically significant difference between the CR+VGPR and SD+PD groups is shown. t: Student’s t-test, M: Mann-Whitney test. Dotted line: fold increase = 3. Samples showing a fold increase in ACTB (which was > 3) were removed from the analysis. Horizontal bars: the mean values.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0128662.g001: Ex vivo mRNA induction in blood obtained prior to bortezomib treatment.The fold increase in (A) LPS-induced GMCSF, (B) ZA-induced GMCSF, (C) LPS-induced CXCL10 (top panel), (D) PHA-induced CCL4, (E) LPS-induced CCL4 and (F) ZA-induced CCL4 (lower panel) mRNA in the CR, VGPR, PR, SD and PD groups is shown. The statistically significant difference between the CR+VGPR and SD+PD groups is shown. t: Student’s t-test, M: Mann-Whitney test. Dotted line: fold increase = 3. Samples showing a fold increase in ACTB (which was > 3) were removed from the analysis. Horizontal bars: the mean values.
Mentions: The fold increase in LPS-induced GMCSF, CXCL10 and CCL4, PHA-induced CCL4 and ZA-induced GMCSF and CCL4 were significantly higher in the CR and VGPR groups than in the SD and PD groups, as determined by both parametric t-tests and non-parametric Mann-Whitney tests, whereas the PR group exhibited an intermediate value (Fig 1). Moreover, 100, 67, 56, 42 and 0% of patients showed more than 3-fold increases in LPS-induced CXCL10 (dotted line in Fig 1).

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