title: Decreased oxygen transfer capacity of erythrocytes as a cause of 5-fluorouracil related ischemia.
abstract: Various mechanisms have been proposed to account for chemotherapy related ischemia, but none of them can explain the available clinical data. In order to explore the possibility that the decreased ability of erythrocytes to deliver oxygen to the heart could be responsible for cardiotoxicity, we have performed an ex vivo and in vivo study of the effects of cisplatin/5-FU on erythrocytes, using a variety of biophysical techniques. Combining EPR and microscopy it was concluded that both cardiotoxic 5-FU and non-cardiotoxic cisplatin have similar effects on the erythrocyte membrane, thus eliminating those changes as a potential source of cardiotoxicity. On the contrary, 31P-NMR and polarography showed that the effects of these cytostatics on the intracellular milieu differ significantly. 5-FU provoked a pronounced decrease of the O2 level in blood and affected the metabolism of phosphate compounds, while cisplatin had no such effects. When combined these two drugs showed synergistic effects, which matches the higher frequency of cardiotoxicity of the combination relative to the sole application of 5-FU. Preliminary results acquired on blood of patients receiving cisplatin/5-FU therapy verified observations obtained ex vivo. These results open a possibility of applying NMR in preclinical trials of new drugs in order to predict their ischemic potential.
authors.affiliation: Institute for Multidisciplinary Research, University of Belgrade, Belgrade, Serbia. ivan@cms.bg.ac.yu
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojević
authors.forename: Svetislav
authors.initials: S
authors.lastname: Jelić
authors.forename: Joanna
authors.initials: J
authors.lastname: Zakrzewska
authors.forename: Goran
authors.initials: G
authors.lastname: Bacić
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects; D004578:Electron Spin Resonance Spectroscopy; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005472:Fluorouracil / Q000009:adverse effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D017202:Myocardial Ischemia / Q000097:blood* / Q000139:chemically induced*; D010100:Oxygen / Q000097:blood* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D002945:Cisplatin; D010100:Oxygen; D005472:Fluorouracil