Immunomodulation by a semiquinone free radical: Evidence implicating T lymphocyte involvement
Date
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Numerous natural and synthetic quinone compounds possess significant anticancer properties. Various mechanisms have been proposed to account for these properties, including tumor cell DNA scission and degradation, intracellular "redox cycling" to cogenerate semiquinone radicals and reactive oxygen intermediates, and the interaction of semiquinone radicals with tumor cell surface membrane flavoenzymes. No evidence has been presented, however, to adequately explain the preferential attack on tumor cells by semiquinone radicals, as opposed to normal cells.
To address this question, an immunologic interaction was examined. A therapy of Ehriich ascites tumor, consisting of a mixture of 750 mM L-ascorbate and 3 mM 2,6- dimethoxy-p-benzoquinone as described by R. Pethig and associates, was used for in vitro and in vivo evaluation. This therapy was employed to generate micromolar quantities of a long-lived semiquinone radical and was found to exert a transient in vivo cytostatic influence against the tumor cells. This semiquinone radical was further found to be ineffective in immunodeficient BALB/c mice at mediating tumor regression. The radical was ineffective in sublethally irradiated mice, in cyclosporin A-treated mice, and in athymic mice. The antitumor efficacy of the radical was maintained, however, in selenium-deficient mice. These results suggested that the antitumor effect of the radical was immunologically mediated, with the T lymphocyte as the primary cellular candidate.
BALB/c mice were depleted of functional T lymphocytes by xenogeneic monoclonal antibody pretreatment, challenged with the tumor, and treated with the semiquinone radicalgenerating therapy. Mice depleted of CD4+ T lymphocytes responded with enhanced tumor progression and significant decreases in life expectancies over controls. Less severe responses were observed in mice devoid of CD8+ T lymphocytes. Mice depleted of both T subpopulations responded with very rapid tumor growth and mortalities. When tumor challenge occurred after the treatment, mice enriched for CD4+ T lymphocytes delayed tumor progression and demonstrated significant increases in life expectancies over controls. The immunologic component of the semiquinone radical interaction hypothesis was clearly shown to be the T helper/inducer lymphocyte, indicating a synergistic phenomenon of radical-induced cytostasis and immunomodulation of T lymphocyte helper activity to promote the inhibition of tumor progression.