**3. Management & preventive strategies for doxorubicin cardiotoxicity**

The DOX has an extreme side effect like cardiotoxicity, but is still in use because of its efficacy in the treatment of cancers. Toxicity can be avoided in several ways. Many studies have shown that cardioprotective agents can achieve a reduction in cardiotoxicity. A recent research on HSP-20 (heat-shock protein) has shown that the protection of Akt activity prevents the cardiotoxic effect caused by DOX [89–92]. Different kind of agents is used to control the DOX effects such as Dexrazoxane (DZR); it contains bisdioxopiperazine rings falling under alpha-amino acid and the derivative compound also known as cardioxane or Totect or Zincard. A promising compound that activates after hydrolysis and resembles the EDTA structure after conversion makes complexes with Iron and reduces the incidence of anthracyclineiron complexes, thus preventing ROS generation in myocytes. Dexrazoxane has also been known to contain the Topoisomerase II enzyme function and inhibit the tumour cell growth. Used mainly for the activities of iron-chelating agent, cardiac protection, anti-neoplastic activities, and chemo protection. Indirectly active in chromatin remodelling complexes by activating vitamin D receptors. DZR is often known to provide up-regulation of the ERK and Akt pathways to guard against cardiomyopathy [93–96] but DZR is not approved for routine use in patients with metastatic cancer and other forms of cancer, as stated by the American Clinical Oncology Society [97, 98]. DOX was analysed in association with DZR for 10 years in women with breast cancer [99]. No, people suffer from heart disease over the time and there are no records of adverse effects with respect to the heart.

Diuretics are used to avoid signs of systemic and pulmonary ventricular obstruction, and medications dependent on β-adrenergic receptors are used depending on the type of systolic heart problem [100]. Metoprolol is safe and effective in the treatment of cardiac myopathy [97], angiotensin II is also recommended for advanced heart disease cases, and low-dose isosorbide dinitrate substituted angiotensin inhibitor medication is favoured and hydralazine is favoured for cardiomyopathic myopathy.

The successful release of DOX at a particular site of operation is another form of preventive step. Like liposomal dosage formulations, the specified delivery mechanism passively decreases the impact caused by non-cancerous cells. For liposomes drug interaction with blood and cancer cells, structural characteristics such as vesicle size, pharmacokinetic characteristics such as stability and pharmacodynamic characteristics such as plasma clearance are important. Tumour cells have conditions that favour high-level depositions, because newly developed cells have microvasculature-permeable vessels, which contain poor lymphatic drainage, low levels of lipase enzymes and other oxidising agents. Due to these features of cancer cells shows aggregation. Once liposomes enter the tumour cells the differences in the intestinal pH favours the release of drugs constituents. The pH of cancer cells is differ from other normal cells because of this the drug is preferentially released in tumour cells and avoid the toxicity in non-cancer cells. The recently reported formulation of polyethylene glycol-coated liposomal doxorubicin (PLD) shows better pharmacokinetics relative to general formulations and has fewer side effects [101]. A phase clinical trial of 50 mg/m2 PLD administration in patients with carcinoma with a demonstrated history of platinum-based chemotherapy at intervals of 4 weeks reported low toxicity. The other formulation like poly (ethylene oxide)-bpoly (e-caprolactone-DOX) [PEO-b- P(CL-DOX)] prevents the premature release outside of the tumor cells [102].

The development of analogues is another possible strategy for reducing the toxicity [96], in the case of anthracyclines nuclear targeted and Non-nuclear targeted are two kinds of strategies concerned in the development of non-toxic chemotherapeutic agents. Analogues such as Methoxymorpholinyl doxorubicin (MMDX), sabarubicin and *N*-Benzyladriamycin-14-valerate now under development to reduce the toxicity caused by DOX. In which, MMDX is nuclear-targeted analogue activated by the liver enzyme cytochrome P450 3A and metabolize into a cytotoxic metabolite and degrades slowly [103]. Based on gene therapy expression of cytochrome enzyme activity increased, cytochrome increases the therapeutic

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*Overview on the Side Effects of Doxorubicin DOI: http://dx.doi.org/10.5772/intechopen.94896*

**4. Conclusion**

the efficiency of DOX.

**Acknowledgements**

**Conflict of interest**

potency of the DOX. The sabarubicin (disaccharide analogue) is also another nuclear targeted molecule that has improved efficiency especially used in case of lung and gynaecological cancer [104]. This stimulates the NF-kB transcription factor, which happens earlier as DNA is involved with multiple tumorogenesis, regulating the expressions of differentiation, variations, cell adhesion and apoptosis [105]. N-Benzyladriamycin-14-valerate is a non-nuclear target molecule obtained by modification of the C-3 amino group and the C-14 position [106]. The compound has comparable activity to DOX but is theoretically more effective than DOX by activating the protein kinase enzyme resulting in cardio-protective activity.

Even DOX used for treating several types of cancers as a result of its wide range of pharmacological activities, but at the same time it causes a wide range of side effects. The major side effects caused by DOX are: carditoxicity, neuropathy, hepatotoxicity, nephrotoxicity, alopecia, typhlitis, myelosuppression, neutropenia, anaemia, and thrombocytopenia. DOX increasing the oxidative stress, decrease the GSH, vitamin E levels, and activates the NF-kB levels causes' hepatotoxicity. Besides, it interferes with the glandular podocytes of the kidney and cause nephropathy. Also, it induces generation of MDA, TBARS, and HNA which decrease the mitochondrial activities and increase in ROS generation causes cell necrosis. Moreover, it causes induction of brain natriuretic peptides, atrial natriuretic peptides genes, mono oxygenases, cytochrome P genes; binds to the cardiolipin, the increase in TLR-4 expression, generation of ROS led to several pathological changes in myocytes causes cardiomyopathy. Several strategies are made to manage and decrease DOX's cardiotoxicity effects, includes a change in the dosage forms for efficacious delivery systems, administration along with anti-oxidants, DZR, diuretics and β-adrenergic agents, and development of different analogues for increasing

The author is grateful to Prof. M. Sarangapani, Principal of University College of

pharmaceutical sciences, Kakatiya University, Warangal.

The author declares no conflict of interest.

*Overview on the Side Effects of Doxorubicin DOI: http://dx.doi.org/10.5772/intechopen.94896*

potency of the DOX. The sabarubicin (disaccharide analogue) is also another nuclear targeted molecule that has improved efficiency especially used in case of lung and gynaecological cancer [104]. This stimulates the NF-kB transcription factor, which happens earlier as DNA is involved with multiple tumorogenesis, regulating the expressions of differentiation, variations, cell adhesion and apoptosis [105]. N-Benzyladriamycin-14-valerate is a non-nuclear target molecule obtained by modification of the C-3 amino group and the C-14 position [106]. The compound has comparable activity to DOX but is theoretically more effective than DOX by activating the protein kinase enzyme resulting in cardio-protective activity.
