title: Cardiac toxicity and antitumor activity of 4'-deoxy-4'-iodo-doxorubicinol.
abstract: The acute and chronic cardiotoxicity as well as the cytotoxicity of 4'-deoxy-4'-iodo-doxorubicinol (I-DXRol), the major metabolite of the doxorubicin (DXR) derivative 4'-deoxy-4'-iodo-DXR (I-DXR), were compared with those of I-DXR and DXR. In the acute study, anesthetized rats received i.v. DXR (10 mg/kg), I-DXR (4 mg/kg), or I-DXRol (4 mg/kg) and were monitored for ECG (S alpha T segment and T wave), systolic (SBP) and diastolic (DBP) blood pressure, the first derivative of the systemic arterial pressure (SA dP/dtmax), and heart rate. Treatments induced a significant widening of the S alpha T segment, but I-DXRol was significantly less toxic than I-DXR or DXR. As compared with control values, DXR induced a marked increase in SBP and DBP and a decrease in SA dP/dtmax, whereas I-DXR and I-DXRol induced modest changes in hemodynamic parameters. In the chronic study, 3 mg/kg DXR given to rats by i.v. bolus once a week for 3 weeks resulted in severe chronic cardiotoxicity that lasted 6 weeks and was characterized by S alpha T-segment widening, T-wave flattening, and severe cardiac histological damage. Doses of 1.2 mg/kg I-DXR and 1.2 and 2.4 mg/kg I-DXRol, given i.v. once a week for 3 weeks, and 3.6 mg/kg I-DXRol given as a single dose were associated with a significant T-wave voltage reduction; I-DXR and 2.4 mg/kg I-DXRol induced significant histological alterations of cardiac tissue as compared with control values, whereas modest alterations of heart tissue were observed after injections of 1.2 and 3.6 mg/kg I-DXRol in three doses and in a single dose, respectively. The cytotoxicity of the three anthracyclines against one glioblastoma cell line and two human small-cell lung cancer lines was similar. Results indicate that the acute cardiotoxicity of I-DXRol is lower than that of I-DXR and DXR, whereas the chronic heart damage is similar to that induced by I-DXR and significantly lower compared than that caused by DXR. Moreover, the cytotoxicity of the metabolite appears to be similar to that of I-DXR and DXR. The lack of additional cardiac toxicity due to I-DXRol further supports the lower overall cardiac toxicity of I-DXR, which retains a cytotoxic activity similar to that of the parent drug.
authors.affiliation: Institute of Medical Pharmacology, University of Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: A
authors.initials: A
authors.lastname: Marchetti
authors.forename: N
authors.initials: N
authors.lastname: Bernardini
authors.forename: R V
authors.initials: RV
authors.lastname: La Rocca
authors.forename: G
authors.initials: G
authors.lastname: Bevilacqua
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000818:Animals; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005910:Glioma / Q000188:drug therapy; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007928:Lethal Dose 50; D008175:Lung Neoplasms / Q000188:drug therapy; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C062054:4'-iodo-4'-deoxydoxorubicinol; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin