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Cancer Chemother Pharmacol (2015) 75:609618
DOI 10.1007/s00280-015-2679-x
ORIGINAL ARTICLE
Myelotoxicity of carboplatin is increased in vivo in db/db mice, the animal model of obesityassociated diabetes mellitus
Krisztina Gresi Attila Megyeri Boglrka Szab Zsolt Szab Jnos Aradi Jzsef Nmeth Ilona Benko
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, granulocytemacrophage 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 inuence 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-uorouracil and 4-thiouridylate.
Results After intraperitoneal administration of carboplatin, each measured characteristics of bone marrow
K. Gresi A. Megyeri J. Nmeth I. Benko (*)
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei blv. 98, Debrecen 4032, Hungarye-mail: [email protected]
B. Szab
Heart and Vascular Center, Semmelweis University, Gal Jzsef 9-11, Budapest 1122, Hungary
Z. Szab
Department of Mathematics and Statistics, CFP AG, Seestrasse 25, 8702 Zollikon, ZH, Switzerland
J. Aradi
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Nagyerdei blv. 98, Debrecen 4032, Hungary
Received: 22 November 2014 / Accepted: 6 January 2015 / Published online: 13 January 2015 Springer-Verlag Berlin Heidelberg 2015
function was more signicantly 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 specic for carboplatin, a similar double to vefold 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...