Ex Vivo Simulation of the Action of Antileukemia Drugs by Measuring Apoptosis-Related mRNA in Blood

Mitsuhashi, Masato; Endo, Katsuya; Obara, Kazuhiko; Izutsu, Hiroshi; Ishida, Taishi; Chikatsu, Norio; Shinagawa, Atsushi

doi:10.1373/clinchem.2007.091975

Cited by 5 publications

(8 citation statements)

References 15 publications

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“…The drug concentrations selected were based on previous studies [26, 27]. One μM of cytarabine is a clinically achievable concentration obtained in situations where a standard dose of cytarabine is administered [28].…”

Section: Resultsmentioning

confidence: 99%

Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1

et al. 2011

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Haem oxygenase-1 (HO-1) is increasingly regarded as a pro-tumoral target in the treatment of human cancers. Currently, little is known about HO-1 and its role in human acute myeloid leukaemia (AML) to regulate apoptosis in response to chemotherapy. Recently, we showed that HO-1 protects AML samples from tumour necrosis factor-α (TNF)-induced apoptosis - it being regulated by transcription factors Nrf2, NF-κB and AP-1. This study aims to analyse the role of HO-1 in regulating apoptosis in AML cells in response to two front-line chemotherapeutic agents used for AML, cytarabine and daunorubicin. Here we show that HO-1 expression in AML samples was increased in response to both cytarabine and daunorubicin treatment, and micro RNA (miRNA) silenced HO-1 expression in combination with either daunorubicin or cytarabine induced a greater apoptotic responses in AML cells. Moreover, we showed that both daunorubicin and cytarabine induced reactive oxygen species (ROS) accumulation to induce apoptosis in AML. However, ROS-dependent induction of HO-1 was limiting the apoptotic response that is seen in AML towards cytarabine and daunorubicin treatment. These findings suggest concurrent inhibition of HO-1 expression in conjunction with chemotherapeutic treatment would improve the number of cases who reach complete remission.

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Section: Resultsmentioning

confidence: 99%

Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1

et al. 2011

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“…Furthermore, in addition to radiation, CDKN1A and BBC3 were used as chemosensitivity markers for aclarubicin, cytarabine, bleomycin, carboplatin, cisplatin, cyclophosphamide, daunorubicin, doxorubicin, fludarabine, idarubicin, methotrexate, pirarubicin, vinblastine, vincristine, vindesine, and etoposide 15,16…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13] Our group has also been focused on the quantification of DNA-damage response using a unique method we developed, 14 and found that CDKN1A and BBC3 were the most sensitive and universal marker mRNA for DNA damage in human whole blood. 15,16 In this study, this assay was used to characterize cancer susceptibility, although we do not know the results in blood samples are representative to other tissues. We chose multiple primary cancer cases as a model of cancer susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Expression of Radiation-induced Leukocyte CDKN1A mRNA in Multiple Primary Breast Cancer Patients: Potential New Marker of cancer susceptibility

et al. 2009

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This study was designed to discover blood biomarkers of cancer susceptibility using invasive multiple (n = 21), single primary breast cancer (n = 21), and control subjects (n = 20). Heparinized whole blood was incubated at 37 °C for 2 hours after 0–10 Gy of radiation, then cell cycle arrest marker CDKN1A and apoptosis marker BBC3 mRNA were quantified. This epidemiological study was practically feasible because radiation-induced mRNA was preserved for at least 1 day whenever blood was stored at 4 °C (r2 = 0.901). Moreover, blood could be stored frozen after radiation treatment (r2 = 0.797). Radiation-induced CDKN1A and BBC3 mRNA were dose dependent, and the degree of induction of CDKN1A was correlated with that of BBC3 (r2 = 0.679). Interestingly, multiple primary cases showed higher induction of CDKN1A mRNA than single primary and control groups, whereas BBC3 did not show such differences. The results suggested that cancer susceptibility represented by the multiple primary breast cancer cases was related to over-reaction of CDKN1A mRNA, not BBC3. The study also suggests that ex vivo gene expression analysis could potentially be used as a new tool in epidemiological studies for cancer and radiation sensitivity research.

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“…As an alternative way, we have previously introduced a novel approach of ex vivo simulation [2][3][4][5], where drugs were directly mixed with heparinized human whole blood for only a couple of hours in test tubes, and drug-induced mRNAs were quantified using a new assay platform we developed [6]. By choosing appropriate target mRNAs, both desired function and unexpected adverse reactions can be determined.…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab-induced CCL20 and interleukin-8 mRNA in human whole blood ex vivo

Hasegawa¹,

Kato²,

Yamaguchi

et al. 2009

Invest New Drugs

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Heparinized human whole blood from 16 adult volunteers was stimulated with achievable blood concentrations of trastuzumab and rituximab at 37 degrees C for 4 h, then CCL20, IL8, and beta-actin mRNA were quantified. The fold increase of beta-actin was all less than 1.5, and heat aggregated IgG induced both IL8 and CCL20 mRNA in all cases, suggesting that the assay was performed appropriately. Rituximab reduced the levels of CCL20 mRNA in approximately 1/3 of subjects, whereas 50 μg/ml trastuzumab induced IL8 and CCL20 mRNA in more than half of subjects. Although the results do not directly indicate the toxicity of antibody medicines, the individual variation found under physiological ex vivo condition will be an interesting clinical research model for drug safety analysis.

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Ex Vivo Simulation of the Action of Antileukemia Drugs by Measuring Apoptosis-Related mRNA in Blood

Cited by 5 publications

References 15 publications

Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1

Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1

Enhanced Expression of Radiation-induced Leukocyte CDKN1A mRNA in Multiple Primary Breast Cancer Patients: Potential New Marker of cancer susceptibility

Trastuzumab-induced CCL20 and interleukin-8 mRNA in human whole blood ex vivo

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