title: Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress.
abstract: This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.
authors.affiliation: Department of Medical Oncology, Policlinico Universitario, University of Cagliari, Strada Statale 554 bivio Sestu, 09042 Monserrato, Italy. mantovan@pacs.unica.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mantovani
authors.forename: Antonio
authors.initials: A
authors.lastname: Macciò
authors.forename: Clelia
authors.initials: C
authors.lastname: Madeddu
authors.forename: Loredana
authors.initials: L
authors.lastname: Mura
authors.forename: Giulia
authors.initials: G
authors.lastname: Gramignano
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Lusso
authors.forename: Elena
authors.initials: E
authors.lastname: Massa
authors.forename: Miria
authors.initials: M
authors.lastname: Mocci
authors.forename: Roberto
authors.initials: R
authors.lastname: Serpe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000494:pharmacology*; D015992:Body Mass Index; D002100:Cachexia; D016022:Case-Control Studies; D002453:Cell Cycle; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016207:Cytokines; D017382:Reactive Oxygen Species