Cardiotoxicity of antitumor agents

In the last few years, cancer chemotherapy has been successfully employed in the treatment of different types of human tumours. Unfortunately, the optimal clinical usefulness of this important treatment modality is usually limited secondary to the development of life-threatening multiple organ toxicity. Cancer chemotherapy may cause these toxic effects by mechanisms not involved in their anticancer activity that can severely affect the life of patients and represent a direct cause of death. Several experimental and clinical studies have demonstrated that some important anticancer drugs interfere with the absorption, synthesis, and excretion of carnitine in non-tumour tissues, resulting in a secondary carnitine deficiency which is reversed by carnitine treatment without affecting anticancer therapeutic efficacy. Prototypes of anticancer drugs that alter carnitine system are doxorubicin, cisplatin, carboplatin, oxaliplatin, cyclophosphamide and ifosfamide. Furthermore, cachectic cancer patients are especially at risk for carnitine deficiency due to decreased oral intake and/or increased renal losses. Altered serum and urine carnitine levels have been reported in cancer patients with various forms of malignant diseases. Recent studies in our laboratory have demonstrated that carnitine deficiency constitute a risk factor and should be viewed as a mechanism during development of oxazaphosphorines-induced cardiotoxicity in rats. Similarly, inhibition of gene expression of heart fatty acid-binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model has been reported. In view of these facts and in view of irreplaceability of these important anticancer drugs, this review aimed to highlight the role of carnitine depletion and supplementation during development of chemotherapy-induced multiple organ toxicity.

This study examined whether doxorubicin therapy alters the expression of heart fatty acid binding protein (H-FABP) and organic cation/carnitine transporter (OCTN2) genes in cardiac tissues, and if so, whether these alterations contributes to doxorubicin-induced cardiotoxicity. Male Wistar albino rats were divided into six groups: group 1 rats were given daily intraperitoneal (i.p.) injections of normal saline for 10 consecutive days; groups 2, 3 and 4 rats were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12, and 18 mg/kg. Rats in the fifth group were injected with l-carnitine (200 mg/kg, i.p.) for 10 consecutive days. Animals in the sixth group received doxorubicin (18 mg/kg) and l-carnitine (200 mg/kg). Treatment with doxorubicin resulted in a significant and dose-dependent decrease in H-FABP and OCTN2 mRNA expression, total carnitine and ATP in cardiac tissues and a significant increase in cardiac enzymes. Moreover, doxorubicin treatment showed significant and dose-dependent increase in the expression of apoptotic genes namely P53 and CD95. Interestingly, carnitine supplementation restored doxorubicin-induced inhibition of gene expression of H-FABP and OCTN2, decrease in myocardial carnitine and ATP to the control values. In conclusion, data from this study suggest that: chronic doxorubicin therapy decreased the expression of H-FABP and OCTN2 mRNA expression in cardiac tissues. The progressive increase in cardiotoxicity enzymatic indices and the decrease in H-FABP and OCTN2 expression may point to the possible contribution of H-FABP and OCTN2 as a mechanism during development of doxorubicin cardiotoxicity.

The major limiting factor in long-term administration of doxorubicin is the development of cumulative dose-dependent cardiomyopathy and congestive heart failure that limit the use of this drug. The present study was undertaken to find out the chemo protective role of methimazole against doxorubicin-induced cardiotoxicity in experimental animals. In the present study, doxorubicin treatment in a dose of 3 mg/kg, i.p., every other day for six doses showed a significant 2.6-, 3- and 10.5-fold increase in the cardiac enzyme activities CK-MB and LDH and troponin-I, respectively, in the serum of the animals. Histopathological investigation of heart tissues showed swollen muscle fibers with interstitial edema and inflammatory exudate. Pretreatment of the animals with methimazole at a dose level of 40 mg/kg, i.p., 30 min before doxorubicin, returned the cardiac enzyme levels to nearly normal value with partial reversal of the inflammatory lesions and the swollen muscle fibers induced by doxorubicin. Moreover, methimazole pretreatment, decreased the doxorubicin level in the heart tissues with a significant increase in plasma level and non significant effect on doxorubicin level in tumor cells. At the same time, methimazole pretreatment did not significantly interfere with the antitumor activity of doxorubicin.

Propionyl- $\text{l}$ -carnitine (PLC) is a naturally occurring compound that has been considered for the treatment of many forms of cardiomyopathies. In this study, the possible mechanisms whereby PLC could protect against adriamycin (ADR)-induced cardiomyopathy were carried out. Administration of ADR (3 mg kg⁻¹i.p., every other day over a period of 2 weeks) resulted in a significant two-fold increase in serum levels of creatine phosphokinase, lactate dehydrogenase and glutamic oxaloacetic transaminase, whereas daily administration of PLC (250 mg kg⁻¹, i.p. for 2 weeks) induced non-significant change. Daily administration of PLC to ADR-treated rats resulted in complete reversal of ADR-induced increase in cardiac enzymes except lactate dehydrogenase which was only reversed by 66%. In cardiac tissue homogenate, ADR caused a significant 53% increase in malonedialdehyde (MDA) and a significant 50% decrease in reduced glutathione (GSH) levels, whereas PLC induced a significant 33% decrease in MDA and a significant 41% increase in GSH levels. Daily administration of PLC to ADR-treated rats completely reversed the increase in MDA and the decrease in GSH induced by ADR to the normal levels. In rat heart mitochondria isolated 24 h after the last dose, ADR induced a significant 48% and 42% decrease in¹⁴CO₂released from the oxidation of [1-¹⁴C]palmitoyl-CoA and [1-¹⁴C]palmitoylcarnitine, respectively, whereas PLC resulted in a significant 66% and 54% increase in the oxidation of both substrates, respectively. Interestingly, administration of PLC to ADR-treated rats resulted in complete recovery of the ADR-induced decrease in the oxidation of both substrates. In addition, in rat heart mitochondria, the oxidation of [1-¹⁴C]pyruvate, [1-¹⁴C]pyruvate and [1-¹⁴C]octanoate were not affected by ADR and/or PLC treatment. Moreover, ADR caused severe histopathological lesions manifested as toxic myocarditis which is protected by PLC. Worth mentioning is that PLC had no effect on the antitumour activity of ADR in solid Ehrlich carcinoma. Results from this study suggest that: (1) in the heart, PLC therapy completely protects against ADR-induced inhibition of mitochondrial β -oxidation of long-chain fatty acids; (2) PLC has and/or induces a powerful antioxidant defense mechanism against ADR-induced lipid peroxidation of cardiac membranes; and finally (3) PLC has no effect on the antitumour activity of ADR.

Failure of chemotherapy with anthracyclines as a result of drug resistance and toxicity is a major problem in the clinical management of neoplasia. The aim of the present study was to evaluate the activity of medroxyprogesterone acetate (MPA) as a chemosensitiser on anthracycline cytotoxicity. The study investigated whether such an effect could be related to an increase in lipid peroxidation, nitric oxide production, membrane fluidity and intracellular anthracycline concentration. The results showed that anthracyclines decreased nitric oxide production but increased membrane viscosity (polarisation constant) and lipid hydroperoxide formation in canine mammary tumour cells. Moreover, it was found that both drug-induced cytotoxicity and membrane viscosity increased in the presence of MPA. Conversely, lipid hydroperoxides decreased in MPA-supplemented cells. Medroxyprogesterone acetate did not show any effect on nitric oxide production. The two anthracyclines used (doxorubicin and idarubicin) showed differential intranuclear accumulation in canine mammary tumour cells, and MPA significantly modified intracellular concentration of anthracyclines.