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

Krisztina Géresi, Klára Benk, Boglárka Szabó, Attila Megyeri, Barna Peitl, Z. Szilvássy, Ilona Benk

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Increased risk of anticancer chemotherapy in seriously obese patients is known. Obesity may be among factors that predict treatment-related toxicity during chemotherapy. We investigated whether functional changes in granulopoiesis may also contribute to increased myelotoxicity in addition to the known alterations of pharmacokinetic parameters in obesity. Hemopoiesis - as measured by cellularity, frequency of granulocyte-macrophage progenitors (CFU-GM) and total CFU-GM content of the femoral bone marrow - did not differ in obese, insulin resistant Zucker rats compared with Wistar rats. Nevertheless increased sensitivity of their CFU-GM progenitor cells to cytotoxic drugs was found by culturing them in vitro in the presence of carboplatin, doxorubicin and 5-fluorouracil. All drugs were more toxic on CFU-GM progenitor cells of insulin resistant Zucker rats than on CFU-GM cells of the control strain. This might be based on metabolic disorders, at least in part, because we could demonstrate a similar increase in toxicity of the studied anticancer drugs to the CFU-GM progenitors originated from the non-obese but insulin resistant Goto-Kakizaki rats in the same dose ranges. After in vivo administration of rosiglitazone, an insulin sensitizer, the anticancer drug sensitivity of CFU-GM progenitors of Goto-Kakizaki rats was decreased concurrently with improvement of insulin resistance. Although the increased treatment-related myelotoxicity and mortality are well-known among obese patients with malignant diseases, only the altered half lives, volumes of distribution and clearances of cytotoxic drugs are thought to be the underlying reasons. According to our knowledge the results presented here, are the first observations about an impaired granulopoiesis in obese animals.

Original languageEnglish
Pages (from-to)172-178
Number of pages7
JournalEuropean Journal of Pharmacology
Volume696
Issue number1-3
DOIs
Publication statusPublished - Dec 5 2012

Fingerprint

Granulocyte-Macrophage Progenitor Cells
Cytotoxins
Insulin
Zucker Rats
Pharmaceutical Preparations
rosiglitazone
Stem Cells
Obesity
Drug Therapy
Poisons
Carboplatin
Thigh
Fluorouracil
Doxorubicin
Insulin Resistance
Wistar Rats
Pharmacokinetics
Bone Marrow
Mortality
Therapeutics

Keywords

  • 5-fluorouracil
  • Carboplatin
  • Doxorubicin
  • Granulocyte-macrophage progenitor cells (CFU-GM)
  • Myelotoxicity
  • Obesity

ASJC Scopus subject areas

  • Pharmacology

Cite this

Toxicity of cytotoxic agents to granulocyte-macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats. / Géresi, Krisztina; Benk, Klára; Szabó, Boglárka; Megyeri, Attila; Peitl, Barna; Szilvássy, Z.; Benk, Ilona.

In: European Journal of Pharmacology, Vol. 696, No. 1-3, 05.12.2012, p. 172-178.

Research output: Contribution to journalArticle

Géresi, Krisztina ; Benk, Klára ; Szabó, Boglárka ; Megyeri, Attila ; Peitl, Barna ; Szilvássy, Z. ; Benk, Ilona. / Toxicity of cytotoxic agents to granulocyte-macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats. In: European Journal of Pharmacology. 2012 ; Vol. 696, No. 1-3. pp. 172-178.
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AU - Szabó, Boglárka

AU - Megyeri, Attila

AU - Peitl, Barna

AU - Szilvássy, Z.

AU - Benk, Ilona

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KW - Myelotoxicity

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