The spin trap alpha-phenyl-tert-butyl nitrone protects against myelotoxicity and cardiotoxicity of adriamycin while preserving the cytotoxic activity.
The possibility of preventing the myelo- and cardiotoxicity of adriamycin (ADR), was explored in in vivo experiments in the rat. Assuming that free radicals play a key role in the ADR organotoxicity, a new anti-radical approach was set up by administering a spin trapping compound (PBN) which is taken up by the cells and specifically interacts with radicals. ADR was given i.v., 3 mg/kg every 3rd day for 3 times. PBN was continuously administered throughout the persistence time of ADR in myocardium (15 days). Serial ECG and leukocyte counting were performed during 10 weeks, then hearts were isolated and Langendorff-perfused; functional parameters (heart rate, contractility, coronary flow) were evaluated. PBN improved ECG and prevented the myelotoxicity, while functional parameters were not significantly different from those of control. Cytotoxicity was evaluated in vitro in 3 different human tumour cell lines; PBN did not modify the cytotoxicity of ADR, thus excluding a free radical involvement in this activity. The present results suggest that a proper administration schedule of spin traps might be a promising approach for improving the therapeutic index of ADR.
Paracchini
L
L
Istituto di Farmacologia Applicata, Università di Milano, Italy.
Jotti
A
A
Bottiroli
G
G
Prosperi
E
E
Supino
R
R
Piccinini
F
F
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005609:Free Radicals; D006321:Heart / Q000187:drug effects*; D007958:Leukocyte Count / Q000187:drug effects; D009589:Nitrogen Oxides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels
D005609:Free Radicals; D009589:Nitrogen Oxides; D013113:Spin Labels; D004317:Doxorubicin