Several mechanisms may lead to oxidative stress (OS) in cancer patients. The first one is the altered energy metabolism which may account for symptoms such as anorexia/cachexia, nausea and vomiting which prevent a normal nutrition and thereby a normal supply of nutrients such as glucose, proteins and vitamins, leading eventually to accumulation of free radicals, which are known as reactive oxygen species (ROS), such as hydroxyl radicals, superoxide radicals and others. The second mechanism is a nonspecific chronic activation of the immune system with an excessive production of proinflammatory cytokines, which in turn may increase the ROS production. Indeed, a chronic inflammatory condition associated with increased OS has been suggested as one of the triggering mechanisms behind the tumor-induced immune suppression. A third mechanism may be the result of antineoplastic drugs administration: many of these drugs, particularly alkylating agents and cisplatin, are able to produce an excess of ROS and therefore lead to OS. In turn, OS plays a significant role in inducing and worsening cancer cachexia. Consistent experimental and clinical data indicate that OS is involved in the pathogenesis of cancer cachexia, although the extent of its contributory role remains to be established. Therefore, OS should be addressed when developing a therapeutic approach for cachectic cancer patients. To counteract ROS and OS several approaches have been tried both in experimental systems and in humans. Among the most used antioxidant agents there are alpha lipoic acid, cysteine-containing compounds, amifostine, reduced glutathione(GSH) and vitamins. Antioxidant vitamins, which include vitamin C, are hypothesized to decrease cancer risk and prevent cancer progression by trapping organic free radicals and/or deactivating reactive oxygen molecules. Indeed, in our previous experimental and clinical studies in advanced-stage cancer patients we demonstrated: 1) the ability of antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cisteine (NAC) to restore in vitro several important T cell functions, and 2) the ability of different antioxidant agents, including vitamin C, used alone or in combination, to reduce in vivo ROS levels and to increase the glutathione peroxidase (GPx) activity. In particular, in two recent studies vitamin C was used as a part of an antioxidant treatment in a combined treatment approach for cancer cachexia. In the first, a Phase II study, the combined treatment approach consisting of antioxidants, including Vitamin C, pharmaconutritional support, progestagen, and an anti-cyclooxygenase-2, resulted in a significant improvement of symptoms of cancer cachexia. In the second, a phase III randomised study, all patients received a basic antioxidant treatment including Vitamin C plus polyphenols, alpha-lipoic acid, carbocysteine, and vitamins A and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. The accrual has been completed and the final results have been submitted for publication.
Vitamin C supplementation in cancer cachexia and related-oxidative stress
MADEDDU, CLELIA;Macció A;
2011-01-01
Abstract
Several mechanisms may lead to oxidative stress (OS) in cancer patients. The first one is the altered energy metabolism which may account for symptoms such as anorexia/cachexia, nausea and vomiting which prevent a normal nutrition and thereby a normal supply of nutrients such as glucose, proteins and vitamins, leading eventually to accumulation of free radicals, which are known as reactive oxygen species (ROS), such as hydroxyl radicals, superoxide radicals and others. The second mechanism is a nonspecific chronic activation of the immune system with an excessive production of proinflammatory cytokines, which in turn may increase the ROS production. Indeed, a chronic inflammatory condition associated with increased OS has been suggested as one of the triggering mechanisms behind the tumor-induced immune suppression. A third mechanism may be the result of antineoplastic drugs administration: many of these drugs, particularly alkylating agents and cisplatin, are able to produce an excess of ROS and therefore lead to OS. In turn, OS plays a significant role in inducing and worsening cancer cachexia. Consistent experimental and clinical data indicate that OS is involved in the pathogenesis of cancer cachexia, although the extent of its contributory role remains to be established. Therefore, OS should be addressed when developing a therapeutic approach for cachectic cancer patients. To counteract ROS and OS several approaches have been tried both in experimental systems and in humans. Among the most used antioxidant agents there are alpha lipoic acid, cysteine-containing compounds, amifostine, reduced glutathione(GSH) and vitamins. Antioxidant vitamins, which include vitamin C, are hypothesized to decrease cancer risk and prevent cancer progression by trapping organic free radicals and/or deactivating reactive oxygen molecules. Indeed, in our previous experimental and clinical studies in advanced-stage cancer patients we demonstrated: 1) the ability of antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cisteine (NAC) to restore in vitro several important T cell functions, and 2) the ability of different antioxidant agents, including vitamin C, used alone or in combination, to reduce in vivo ROS levels and to increase the glutathione peroxidase (GPx) activity. In particular, in two recent studies vitamin C was used as a part of an antioxidant treatment in a combined treatment approach for cancer cachexia. In the first, a Phase II study, the combined treatment approach consisting of antioxidants, including Vitamin C, pharmaconutritional support, progestagen, and an anti-cyclooxygenase-2, resulted in a significant improvement of symptoms of cancer cachexia. In the second, a phase III randomised study, all patients received a basic antioxidant treatment including Vitamin C plus polyphenols, alpha-lipoic acid, carbocysteine, and vitamins A and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. The accrual has been completed and the final results have been submitted for publication.
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