Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity

Matsumura-Takeda, Kuniko; Kotosai, K.; Ozaki, Atsushi; Hara, Hiroshi; Yamashita, Shuji

doi:10.1016/s0278-6915(02)00048-0

Cited by 9 publications

(6 citation statements)

References 20 publications

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“…The in vitro bone marrow colony-formation assay is also useful to investigate potential species differences in heme toxicity (43,44), LY2857785 was tested in normal hematopoietic progenitor cells from rats and dogs and potent antiproliferation was observed in both species cells following in vitro treatment (data not shown). Human bone marrow cells, however, were found to be less sensitive (2-to 5-fold) than those of rats and dogs.…”

Section: Discussionmentioning

confidence: 99%

“…3C) was selective against malignant versus normal proliferating cells, LY2857785 was evaluated in the human bone marrow myeloid progenitor colony formation assay (CFU-GM). The hematopoietic colony formation assay is a relevant model to assess potential toxic effects of new compounds in proliferating normal human cells (42)(43)(44), and the assay has been validated as an in vitro model to estimate maximum tolerated dose levels in humans for cytotoxic agents (45,46).…”

Section: Ly2857785 Inhibits Proliferation Of Normal Human Hematopoietmentioning

confidence: 99%

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A Novel CDK9 Inhibitor Shows Potent Antitumor Efficacy in Preclinical Hematologic Tumor Models

Yin

Lallena

Kreklau

et al. 2014

Molecular Cancer Therapeutics

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DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, including CDK9, are serine/threonine kinases known to regulate transcriptional initiation and elongation by phosphorylating Ser 2, 5, and 7 residues on CTD. Given the reported dysregulation of these kinases in some cancers, we asked whether inhibiting CDK9 may induce stress response and preferentially kill tumor cells. Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. This molecule inhibits the growth of a broad panel of cancer cell lines, and is particularly efficacious in leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. Thus, inhibition of CDK9 may represent an interesting approach as a cancer therapeutic target, especially in hematologic malignancies.

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Section: Discussionmentioning

confidence: 99%

Section: Ly2857785 Inhibits Proliferation Of Normal Human Hematopoietmentioning

confidence: 99%

A Novel CDK9 Inhibitor Shows Potent Antitumor Efficacy in Preclinical Hematologic Tumor Models

Yin

Lallena

Kreklau

et al. 2014

Molecular Cancer Therapeutics

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“…Mature granulocytes are not significantly affected; however, cytotoxic fungal metabolites have been shown to cause a decrease in the immature myelocyte count 23 . Decreases in blood cell counts and bone marrow hypoplasia are well known to be caused by 5-FU administration 18–20 . Drug-induced myelotoxicity has been shown in short-term studies 24,25 .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Myelotoxicity in Dietary Restricted Rats

et al. 2009

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The purpose of this study was to clarify the effect of decreased food consumption on evaluation of myelotoxicity in routine general toxicity studies. Male rats were divided into the following 7 groups: 12, 15, and 18 mg/kg 5-fluorouracil (5-FU) treatment groups (FU12, FU15 and FU18); dietary restriction groups (R12, R15 and R18 receiving the same amount of food as the rats in the FU12, FU15 and FU18 groups, respectively); and a nontreated control group (NT). We compared the changes in body weight, hematology and the results of cytological analyses of bone marrow and histopathology among the groups after administration and recovery periods of 14 and 7 days, respectively. At the end of the administration period, the FU15 and FU18 groups showed decreases in many hematologic and bone marrow parameters that were all similar to those in the corresponding dietary restriction groups (R15 and R18). A granulocyte abnormality (polyploidy: frequency of 1% or less) was also observed in all 5-FU treated groups. At the end of the recovery period, increases in the reticulocyte and platelet counts and extramedullary hematopoiesis of the spleen were observed in the 5-FU treated groups. These results indicate that the results of general toxicity studies in rats should be evaluated in consideration of dietary restriction effects when food consumption is decreased at about 30-40% or more. Careful morphological observation of hemocytes would be helpful in distinguishing the effect of a drug from that of dietary restriction in relation to hematological and bone marrow parameters. Performance of a recovery test to determine the reactive response of hematopoiesis is also recommended.

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“…29 Bone marrow cells were collected from the femurs of rats by flushing dissected and cleaned femurs with α-medium (GIBCO BRL, Gaithersburg, MD) containing 10% fetal bovine serum. The cells were collected and then incubated for 2 h. The nonadherent cells were passed through a 40-µm cell strainer (Becton Dickinson Labware, Franklin Lakes, NJ) to prepare single cell suspensions.…”

Section: Methodsmentioning

confidence: 99%

Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel‐Induced Hematopoietic Toxicity

Yamada

Maeda

Kiyotani

et al. 2014

CPT Pharmacom & Syst Pharma

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Neutropenia is a lethal dose-limiting toxicity of docetaxel. Our previous report indicated that the prevalence of severe docetaxel-induced neutropenia is significantly associated with genetic polymorphisms in solute carrier organic anion transporter 1B3 (SLCO1B3) (encoding organic anion–transporting polypeptide 1B3 (OATP1B3)) and ATP-binding cassette subfamily C2 (ABCC2) (encoding multidrug-resistant–associated protein 2 (MRP2)). Therefore, we investigated their significance in docetaxel-induced neutropenia. In vitro experiments suggested their possible involvement in the hepatic uptake of docetaxel and its efflux from bone marrow cells. To further characterize a quantitative impact of OATP1B3 and MRP2 on neutropenia, we used an in silico simulation of the neutrophil count in docetaxel-treated subjects with functional changes in OATP1B3 and MRP2 in a pharmacokinetic/pharmacodynamic model. The clinically reported odds ratios for docetaxel-induced neutropenia risk were explained by the decreased function of OATP1B3 and MRP2 to 41 and 32%, respectively. These results suggest that reduced activities of OATP1B3 and MRP2 associated with systemic exposure and local accumulation in bone marrow cells, respectively, account for the docetaxel-induced neutropenia observed clinically.

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Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity

Cited by 9 publications

References 20 publications

A Novel CDK9 Inhibitor Shows Potent Antitumor Efficacy in Preclinical Hematologic Tumor Models

A Novel CDK9 Inhibitor Shows Potent Antitumor Efficacy in Preclinical Hematologic Tumor Models

Evaluation of Myelotoxicity in Dietary Restricted Rats

Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel‐Induced Hematopoietic Toxicity

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