Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy.

Metastatic cancers are associated with cellular oxidative stress, and during cancer chemotherapy excess drug-induced oxidative stress can limit therapeutic effectiveness and cause a number of side effects, including fatigue, nausea, vomiting, diarrhea and more serious adverse effects, such as cardiomyopathy, peripheral neuropathy, hepatotoxicity and pulmonary fibrosis. We review here the hypothesis that the acute and chronic adverse effects of cancer chemotherapy can be reduced by molecular replacement of membrane lipids and enzymatic cofactors, such as coenzyme Q(10). By administering nutritional supplements with replacement molecules and antioxidants, oxidative membrane damage and reductions of cofactors in normal tissues can be reversed, protecting and restoring mitochondrial and other cellular functions and reducing chemotherapy adverse effects. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefit of molecular replacement plus antioxidants in reducing the damage to mitochondrial membranes, restoring mitochondrial electron transport function, reducing fatigue and protecting cellular structures and enzymes from oxidative damage. Molecular replacement and antioxidant administration mitigates the damage to normal tissues, such as cardiac tissue, and reduces the adverse effects of cancer therapy without reduction in therapeutic results.

Molecular Replacement for Cancer Metabolic and Mitochondrial Dysfunction, Fatigue and the Adverse Effects of Cancer Therapy.

During cancer treatment drug-induced oxidative stress can limit the effectiveness of therapy and cause a number of side effects such as fatigue, nausea, vomiting and diarrhea, as well as more serious adverse effects including cardiomyopathy, peripheral neuropathy, hepatotoxicity and pulmonary fibrosis. Many of these adverse effects are due to oxidative stress-mediated damage to normal tissues. Antioxidant administration and molecular replacement can mitigate the damage to normal tissues and reduce the adverse effects of cancer therapy without loss of therapeutic potential. For example, loss of efficiency in the electron transport chain caused by membrane peroxidation and reduction in coenzyme Q10 can occur during cytotoxic therapy. Molecular replacement of membrane lipids and enzymatic cofactors administered as nutritional supplements with antioxidants can prevent oxidative membrane damage and reduction of cofactors in normal tissues, restore mitochondrial and other cellular functions and reduce the adverse effects of cancer therapy. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefit of Molecular Replacement Therapy plus antioxidants in restoring mitochondrial electron transport function, reducing moderate to severe chronic fatigue and protecting mitochondrial and other cellular structures and enzymes from oxidative or other damage due to cytotoxic therapy.

Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity.

Preclinical and clinical studies suggest that anthracycline-induced cardiotoxicity can be prevented by administering coenzyme Q10 during cancer chemotherapy that includes drugs such as doxorubicin and daunorubicin. Studies further suggest that coenzyme Q10 does not interfere with the antineoplastic action of anthracyclines and might even enhance their anticancer effects. Preventing cardiotoxicity might allow for escalation of the anthracycline dose, which would further enhance the anticancer effects. Based on clinical investigation, although limited, a cumulative dose of doxorubicin of up to 900 mg/m2, and possibly higher, can be administered safely during chemotherapy as long as coenzyme Q10 is administered concurrently. The etiology of the dose-limiting cardiomyopathy that is induced by anthracyclines can be explained by irreversible damage to heart cell mitochondria, which differ from mitochondria of other cells in that they possess a unique enzyme on the inner mitochondrial membrane. This enzyme reduces anthracyclines to their semiquinones, resulting in severe oxidative stress, disruption of mitochondrial energetics, and irreversible damage to mitochondrial DNA. Damage to mitochondrial DNA blocks the regenerative capability of the organelle and ultimately leads to apoptosis or necrosis of myocytes. Coenzyme Q10, an essential component of the electron transport system and a potent intracellular antioxidant, appears to prevent damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy.

Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness.

Antineoplastic agents induce oxidative stress in biological systems. During cancer chemotherapy, oxidative stress-induced lipid peroxidation generates numerous electrophilic aldehydes that can attack many cellular targets. These products of oxidative stress can slow cell cycle progression of cancer cells and cause cell cycle checkpoint arrest, effects that may interfere with the ability of anticancer drugs to kill cancer cells. The aldehydes may also inhibit drug-induced apoptosis (programmed cell death) by inactivating death receptors and inhibiting caspase activity. These effects would also diminish the efficacy of the treatment. The use of anti-oxidants during chemotherapy may enhance therapy by reducing the generation of oxidative stress-induced aldehydes.

Dietary polyunsaturated fatty acids: impact on cancer chemotherapy and radiation.

Preclinical studies have shown that certain polyunsaturated fatty acids may actually enhance the cytotoxicity of several antineoplastic agents and the anticancer effects of radiotherapy. These effects are possibly mediated by incorporation of the polyunsaturated fatty acids into cancer cell membranes, thus altering the physical and functional properties. In addition, certain polyunsaturated fatty acids may also reduce or prevent some of the side effects of these therapies, and administering antioxidants to prevent polyunsaturated fatty acid-induced oxidative stress may further enhance the impact of chemotherapy and radiation.