Toxicity of cytotoxic agents to granulocyte–macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats

Géresi, Krisztina; Benkö, K.; Szabo, Barbara; Megyeri, A; Peitl, Barna; Szilvássy, Zoltán; Benkö, Ilona

doi:10.1016/j.ejphar.2012.09.018

Cited by 5 publications

(6 citation statements)

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“…We also demonstrated that CFU-GM progenitors of Goto-Kakizaki rats had higher sensitivity against carboplatin, and doxorubicin and 5-fluorouracil in vitro than CFU-GM cells of non-insulin resistant control rats [15]. Goto-Kakizaki rats are non-obese but insulin resistant animals thus our results suggest that insulin resistance may involve CFU-GM progenitor cells.…”

Section: Page 16 Of 33 Cancer Chemotherapy and Pharmacologysupporting

confidence: 51%

“…Although there was no difference between the obese and the lean control animals in number and proliferation of the haemopoietic progenitors in bone marrow, in vitro exposure to carboplatin, doxorubicin and 5-fluorouracil showed higher sensitivity of CFU-GM progenitors from Zucker obese rats to the toxicity of anticancer drugs than in bone marrow cells from control rats. According to our in vitro model the therapyrelated myelotoxicity might be not only due to the different pharmacokinetic parameters or changes in drug exposure but also to the dysfunction of haemopoietic progenitor cells [15].…”

Section: Discussionmentioning

confidence: 99%

“…This suggested that insulin resistance may influence bone marrow functions and may alter therapyrelated toxicity of anticancer drugs. Later, we were the first to observe an increased in vitro toxicity of cytotoxic drugs to the granulocyte-macrophage progenitors in Zucker obese rats with insulin resistance and also in non-obese but insulin resistant Goto-Kakizaki rats [15].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, it is also accepted that obesity may have an effect on myelotoxicity of anticancer treatment not only through pharmacokinetic but also through pharmacodynamic mechanisms [3,15]. One of the best characterized and most frequent metabolic dysfunction in obesity is insulin resistance which is also a characteristic of diabetes mellitus type 2 (DMT2).…”

Section: Introductionmentioning

confidence: 99%

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Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

Géresi

Megyeri

Szabo

et al. 2015

Cancer Chemother Pharmacol

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PurposeSome authors observed increased carboplatin-associated myelotoxicity in obese patients which was exclusively attributed to elevated AUC. To investigate the potential contribution of functional changes of cells primarily responsible for myelopoiesis, granulocyte-macrophage progenitors (CFU-GM) were studied in obesity-associated diabetes mellitus (DMT2). MethodsThe most frequently used animal model of human obesity with DMT2 is db/db mouse. Cellularity, frequency of CFU-GM and total CFU-GM content of femoral bone marrow was measured after 100 mg/kg dose of carboplatin in vivo. To exclude influence of pharmacokinetic changes direct toxicity of carboplatin on CFU-GM was also determined in vitro and was compared with other anticancer agents, namely doxorubicin, 5-fluorouracil and 4-thiouridylate. ResultsAfter intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function were more significantly suppressed and the induced neutropenia were more serious in db/db mice than in the controls. The increased myelotoxicity seemed to be a direct effect on myeloid progenitor cells since their increased in vitro sensitivity was found in db/db mice. This was not specific for carboplatin, a similar double to 5-fold increase in myelotoxicity of each cytotoxic drug with different mechanism of action was observed. Four-thiouridylate, a promising antileukemic molecule with good therapeutic index, was by far the least toxic for CFU-GM of db/db mice.Conclusions A serious disorder of CFU-GM progenitors was suggested in obese mice with DMT2, which eventually might lead to more severe myelotoxicity and neutropenia. Weight loss and normalization of glucose homeostasis may be important before chemotherapy of malignant diseases in obesity with DMT2.

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Section: Page 16 Of 33 Cancer Chemotherapy and Pharmacologysupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

Géresi

Megyeri

Szabo

et al. 2015

Cancer Chemother Pharmacol

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“…These observations suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissue than their lean counterparts. Previous studies have also demonstrated that anticancer agent-induced myelotoxicity is more severe in rodent models of obesity including obese Zucker rats and db/db mice, than in controls (Géresi et al, 2012(Géresi et al, , 2015. In addition, recent epidemiological studies have shown that obesity is significantly associated with iron deficiency, leading to anemia (Becker et al, 2015;Zhao et al, 2015).…”

Section: Discussionmentioning

confidence: 98%

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol

et al. 2017

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-3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in highrisk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 9, 28.5, 90, 285, or 900 ppm 3-MCPD in drinking water for 13 weeks. 3-MCPD treatment decreased body weight gain, increased relative kidney weights, induced anemia, and induced epithelial cell necrosis in epididymal ducts in all 3 strains. The degrees of epididymal damage were higher in F344 and lean rats than in fatty rats, while renal toxicity was most potent in F344 rats and comparable in lean and fatty rats. In contrast, the hematology data indicated that anemia was worse in fatty rats than in F344 and lean rats, and a significant decrease in hematopoietic cells in the bone marrow was observed only in fatty rats. The no-observed-adverse-effect level was estimated to be 28.5 ppm in all 3 strains for 3-MCPD. These results suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissues than their lean counterparts.

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P-selectin glycoprotein ligand-1 deficiency augments G-CSF induced myeloid cell mobilization

Miszti-Blasius

Felszeghy

Kiss

et al. 2013

Naunyn-Schmiedeberg's Arch Pharmacol

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The effect of granulocyte colony-stimulating factor (G-CSF) was investigated in P-selectin glycoprotein ligand-1 (PSGL-1) deficient (PSGL-1(-/-)) and wild-type (PSGL-1(+/+)) mice to establish the role of this mucin in myeloid cell mobilization. G-CSF activates tissue proteases that cleave adhesion molecules, thus enhances the mobilization of myeloid cells and haematopoietic stem cells. Cytopenia was induced with a single dose of cyclophosphamide. In PSGL-1(-/-) animals, we observed a delayed extravasation of mature myeloid cells from the peripheral vessels into the tissue compartments and their faster mobilization from the bone marrow. Subsequently, animals received G-CSF twice a day for 4 days. Neutrophil and monocyte counts increased upon completion of G-CSF treatment and both values were significantly higher in PSGL-1(-/-) mice; 47.7 versus 28.3 G/l for neutrophils and 4.1 versus 2.0 G/l for monocytes. The ratio of atypical myeloid cells was also elevated. Analyzing the causes of the above differences, we identified a 4-fold increase in the colony-forming unit (CFU-GM) counts of the peripheral blood in PSGL-1(-/-) mice, compared to wild-type animals. A significantly elevated number of CFU-GM was detected also in the femurs of PSGL-1(-/-) mice, 4 and 5 days after cyclophosphamide treatment and these values paralleled with the elevation of CD34+/CD117+ stem cell counts in the peripheral blood. Our data suggest, that in the absence of PSGL-1, G-CSF was more potent in elevating absolute myeloid cell numbers by acting on cell release from the bone marrow, maturation from circulating precursor cells in the peripheral blood and prolonged retainment in the circulation.

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Toxicity of cytotoxic agents to granulocyte–macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats

Cited by 5 publications

References 33 publications

Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol

P-selectin glycoprotein ligand-1 deficiency augments G-CSF induced myeloid cell mobilization

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