No abstract

The premise of this study is that mitochondrial lesions caused by anthracyclines lead directly to cardiotoxicity. We compared several biochemical parameters, including endogenous cellular respiration, adenosine and guanosine triphosphate levels, and ¹⁴C-amino acid incorporation, of rat hearts treated with doxorubicin and some of its derivatives, recent products of pharmacological research aimed at selecting less toxic antiblastic agents. In rats treated in vivo, we further examined the ultrastructural changes induced by anthracycline antibiotics in order to elucidate which biochemical parameters were consistent with the morphological lesions. Our data indicate that mitochondria are the target of the anthracycline effects and that oxygen uptake and nucleotide levels may be regarded as markers of the toxicity when evaluating new drugs before their clinical use. The lack of cytoplasmatic or endoplasmatic reticulum alterations may account for the failure of anthracyclines to affect amino acid incorporation. In any event, the rate of protein synthesis cannot serve as a marker of cardiac toxicity. In this context, epidoxorubicin and iododoxorubicin are two derivatives characterized by less cardiotoxic potential than doxorubicin and thus appear to be promising antiblastic agents.

Anthracycline derivatives are among the most effective and widely used antiblastic drugs. Irreversible and dose-dependent cardiotoxic side effects, however, severely limit their prolonged use. This study sought to establish whether carnitine derivatives or coenzyme Q₁₀ could provide protection against doxorubicin-related cardiac damage. Rat heart slices were incubated for 60 min in a Warburg apparatus at 38°C with 4 mM L-carnitine or 1 mM propionyl carnitine or 15 μM coenzyme Q₁₀ to which 25 μM doxorubicin was added. Cellular oxygen uptake and ¹⁴C-leucine incorporation were measured. Carnitine derivatives significantly reduced (p < 0.001) the metabolic cardiac impairment due to doxorubicin. Incubation for 60 min with a mixture of L-carnitine and doxorubicin improved cellular respiration, oxygen uptake being only 9% less than that of the controls, and an even greater reversal characterized the propionyl carnitine mixture for which the recovery of endogenous cellular respiration was almost complete (93%). Coenzyme Q₁₀ instead provided no significant protection against doxorubicin-induced inhibition. The incorporation of ¹⁴C-leucine followed a similar pattern; the addition of carnitine derivatives to doxorubicin served to restore cellular protein synthesis almost totally (from 76 to 97%), whereas coenzyme Q10 produced no significant increment, probably due to the low permeability of the cell membrane to exogenous coenzyme Q₁₀. Thus, levo and propionyl carnitine even more appear to be promising agents in the prevention of doxorubicin-related cardiac toxicity.