The in vivo antitumor activity of vitamin C : K3 combinations against human prostate cancer correlates with their abilities to reactivate DNases

JM Jamison, PhD a, HS Taper, MD, PhDb, J Gilloteaux, DSca, JL Summers, MD, PhDa

<sup>a Department of Urology, Summa Health System / N.E. Ohio Univ. Coll. of Med, Rootstown, Ohio United States <sup>b Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, The Catholic University of Louvain, Brussels, Belgium

AIM: To measure the effect of vitamin C (VC) and K3 (VK3) on tumor growth and host organ toxicity in nude mice and to evaluate the role of DNases in tumor cell death. METHODS: Forty male NCr nude mice were injected with 1 x 106 DU145 cells. After tumors developed, the mice were divided into two groups of eight mice for experiment one and into six groups of four mice for experiment two. In experiment 1, one group received oral vitamins (VC = 15 g/l and 0.15 g/l VK3) daily and the other received water. After 3 weeks, the mice were sacrificed and major organs were removed, weighed and prepared for histological examination. In experiment 2, test mice were given the vitamins by oral lavages and i.p. injection. The mice were sacrificed at 1, 2, 4, 8, and 24 h and the tumors were used for light and electron microscopy as well as DNase assays and methyl green staining. RESULTS: Oral vitamins significantly reduced the growth rate of the solid tumors (p < 0.05) without inducing significant bone marrow toxicity, changes in organ weight or pathological changes in these organs. DNase I activity appeared 1 h after vitamin treatment, decreased slightly until 2 h and disappeared by 8 h. DNase II activity appeared 2 h after vitamin treatment, reached its zenith between 4 to 8 h and maintained low activity at 24 h. DNase activity was accompanied by decreased DNA content and a novel form of non-apoptotic tumor cell death (autoschizis). CONCLUSIONS: The vitamin combination reactivated DNases which induced tumor cell death by autoschizis without inducing overt host toxicity.

KEY WORDS: Autoschizis, ascorbate, menadione, oxidative stress, prostate cancer.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Dietary Influences.