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

Krisztina Géresi, Attila Megyeri, Boglárka Szabó, Zsolt Szabó, J. Aradi, J. Németh, Ilona Benko

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: Some 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). Methods: The 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 were 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. Results: After intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function was more significantly suppressed and the induced neutropenia was 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 fivefold 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.

Original languageEnglish
Pages (from-to)609-618
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume75
Issue number3
DOIs
Publication statusPublished - 2015

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Granulocyte-Macrophage Progenitor Cells
Carboplatin
Medical problems
Diabetes Mellitus
Animals
Animal Models
Obesity
Bone
Neutropenia
Pharmacokinetics
Chemotherapy
Macrophages
Poisons
Fluorouracil
Bone Marrow
Antineoplastic Agents
Doxorubicin
Toxicity
Myelopoiesis
Myeloid Progenitor Cells

Keywords

  • 5-Fluorouracil
  • Carboplatin
  • Diabetes mellitus
  • Doxorubicin
  • Granulocyte-macrophage progenitor cells (CFU-GM)
  • Myelotoxicity
  • Obesity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology
  • Medicine(all)

Cite this

Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus. / Géresi, Krisztina; Megyeri, Attila; Szabó, Boglárka; Szabó, Zsolt; Aradi, J.; Németh, J.; Benko, Ilona.

In: Cancer Chemotherapy and Pharmacology, Vol. 75, No. 3, 2015, p. 609-618.

Research output: Contribution to journalArticle

Géresi, Krisztina ; Megyeri, Attila ; Szabó, Boglárka ; Szabó, Zsolt ; Aradi, J. ; Németh, J. ; Benko, Ilona. / Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus. In: Cancer Chemotherapy and Pharmacology. 2015 ; Vol. 75, No. 3. pp. 609-618.
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T1 - Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesity-associated diabetes mellitus

AU - Géresi, Krisztina

AU - Megyeri, Attila

AU - Szabó, Boglárka

AU - Szabó, Zsolt

AU - Aradi, J.

AU - Németh, J.

AU - Benko, Ilona

PY - 2015

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N2 - Purpose: Some 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). Methods: The 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 were 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. Results: After intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function was more significantly suppressed and the induced neutropenia was 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 fivefold 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.

AB - Purpose: Some 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). Methods: The 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 were 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. Results: After intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function was more significantly suppressed and the induced neutropenia was 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 fivefold 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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KW - Doxorubicin

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KW - Obesity

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