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

• Published in: Cancer chemotherapy and pharmacology 2015-03, Vol.75 (3), p.609-618
• Main Authors: Géresi, Krisztina, Megyeri, Attila, Szabó, Boglárka, Szabó, Zsolt, Aradi, János, Németh, József, Benkő, Ilona
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - toxicity; Bone Marrow Diseases - chemically induced; Bone Marrow Diseases - pathology; Cancer Research; Carboplatin - toxicity; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - physiopathology; Disease Models, Animal; Doxorubicin - toxicity; Fluorouracil - toxicity; Granulocyte-Macrophage Progenitor Cells - drug effects; Granulocyte-Macrophage Progenitor Cells - pathology; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Neutropenia - chemically induced; Obesity - complications; Obesity - physiopathology; Oncology; Original Article; Pharmacology/Toxicology; Thionucleotides - toxicity; Uridine Monophosphate - analogs & derivatives; Uridine Monophosphate - toxicity
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2679-x

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.