ABSTRACT
Experiments were performed with K562 erythroleukemia cells to further characterize the observation that hemin protects hemopoietic cells from the cytotoxic effects of anthracycline drugs. The present studies demonstrate that this protective effect of hemin applies only to anthracyclines and not to other classes of antineoplastic agents. Hemin interferes with the cellular accumulation of various anthracyclines, as measured by cytofluorography, and prevents binding of anthracyclines to isolated cell nuclei. Exposure of K562 cells to hemin retards the anthracycline-induced arrest of cells at the G2-M interphase of the cell cycle and permits cells to undergo continuing division as demonstrated by clonal growth in plasma clot cultures. Furthermore, hemin decreases the ability of anthracyclines to unwind simian virus 40 supercoiled DNA in vitro. The protective effect of hemin fails to occur if cells have been preincubated with this agent for 72 h before they are exposed to Adriamycin in the absence of hemin. The findings suggest that hemin prevents anthracycline-induced cytotoxicity by acting at several levels. These effects may be mediated by direct interactions of hemin with DNA and perhaps other cellular constituents or by molecular complex formation between hemin and anthracyclines at intracellular sites.
Subject(s)
Hematopoietic Stem Cells/drug effects , Heme/analogs & derivatives , Hemin/pharmacology , Antibiotics, Antineoplastic , Antineoplastic Agents/antagonists & inhibitors , Antineoplastic Agents/toxicity , Biological Transport/drug effects , Cell Compartmentation/drug effects , Cell Cycle/drug effects , Cell Line , Cell Nucleus/metabolism , Cell Survival/drug effects , DNA/drug effects , DNA Damage , Humans , In Vitro Techniques , Naphthacenes/antagonists & inhibitors , Naphthacenes/metabolism , Naphthacenes/toxicityABSTRACT
Doxorubicin is one of the most effective antineoplastic agents but its limited use is due to acute and chronic cardiotoxicity. These side-effects are irreversible and dose-dependent, occurring in one-third of the patients treated after a cumulative dose of 300 mg/m2. It has been suggested that the problem of acute and chronic cardiotoxicity may be prevented by using L-carnitine. Hence nine patients receiving a cumulative dose (200-490 mg/m2) of doxorubicin have been studied. Acute cardiotoxicity has been evaluated by creatine kinase---marsh bender (MB) serum levels before and 15 h after treatment. Data demonstrated no significant increase of isoenzyme-MB after doxorubicin administration. Chronic cardiotoxicity has been monitored studying the electrocardiograph and the left ventricular performance by computerized M-Mode echocardiography measuring the maximal velocity of circumferential fibre shortening (VCF Max) which is considered a reliable and very sensitive non-invasive parameter to evaluate myocardial contractility. The results show a decrease in VCF Max (measured in diameter/cardiac cycle) from 1.7 +/- 0.4 to 1.4 +/- 0.3 but still within normal values. So the systematic use of L-carnitine as adjuvant therapy is proposed during doxorubicin administration.
