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Scientific Rationale for Using High-Dose Multiple Micronutrients as an Adjunct to Standard and Experimental Cancer Therapies

Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center (K.N.P., W.C.C., B.K.), Denver, Colorado
Department of Pathology, University of California (K.C.P.), San Francisco, California

View larger version (164K): [in a new window]   Fig. 1. Melanoma cells (105) were plated in tissue culture dishes (60 mm), and d--tocopheryl succinate (-TS) and sodium succinate plus ethanol were added to separate cultures 24 hours after plating. Drugs and medium were changed at two and three days after treatment. Photomicrographs were taken four days after treatment. Control cultures showed fibroblastic cells as well as round cells in clumps (a); cultures treated with ethanol (1%) and sodium succinate (5–6 µg/mL) also exhibited fibroblastic morphology with fewer round cells (b); -TS-treated cultures 5 µg/mL (c), and 6 µg/mL (d) showed a dramatic change in morphology [41].

View larger version (11K): [in a new window]   Fig. 2. Effect of vitamin C on growth of human tumorigenic parotid acinar cells in culture (2HPG1). Cells (100,000/60 mm dish) were plated in tissue culture dishes, and freshly prepared sodium ascorbate solution at various concentrations was added 24 hours later. Freshly prepared sodium ascorbate solution and medium were changed after two days of treatment. Growth was determined after three days of treatment. Each value (mean ± SEM) represents an average of nine samples [16].

View larger version (35K): [in a new window]   Fig. 3. Effects of -TS on mitotic accumulation in three human cancer cell lines and three normal human fibroblasts. Decreased mitotic accumulation is seen in cancer cells (A–C), but not in normal fibroblasts (D–F). Each point represents an average of six samples. Significant difference at p = 0.05 was observed in all tumor cell lines (A–C) at 20 µg/mL of -TS at all points in comparison to controls [23].

View larger version (28K): [in a new window]   Fig. 4. Effect of d--tocopheryl succinate (-TS) on the level of radiation-induced chromosomal damage in human cervical cancer (HeLa cells), ovarian carcinoma cell lines (OVG1 and SKOV3) and in human normal skin fibroblasts (GM2149, HF19 and AG1522). -TS treatment alone increased chromosomal damage in all three cancer cell lines, but not in any normal cell lines. -TS treatment also enhanced the levels of radiation-induced chromosomal damage in cancer cells but it protected normal cells against such damage. The bar is standard error of the mean; and the difference between control and experimental groups in cancer cells, and between control (irradiation alone) and experimental groups (irradiation plus -TS) is significant at p = 0.05 [24].

View larger version (31K): [in a new window]   Fig. 5. Neuroblastoma cells (NBP2) were plated in tissue culture dishes (60 mm), and the cells were gamma-irradiated 24 hours after plating. Vitamin E succinate or the solvent (ethanol 0.25% and sodium succinate 5 µg/mL) wag added immediately before irradiation. The drugs and medium were changed after two days of treatment. The number of cells per dish was determined after three days of treatment. Each experiment was repeated at least twice involving three samples per treatment. The average value (172 ± 7 x 104) of untreated control NB cells was considered 100%, and the growth in treated cultures was expressed as a % of untreated controls. The bar at each point is standard error of the mean [1].

View larger version (21K): [in a new window]   Fig. 6. Neuroblastoma cells (NBP2) (50,000 per dish) were plated in tissue culture dishes (60 mm), and vincristine and aqueous preparation of vitamin E (dl--tocopheryl acetate) were added 24 hours later. Drugs and medium were changed two days after treatment. The cell number and the number of trypan blue-stained cells were determined three days after treatment. The number of stained cells was subtracted from the total number of cells to obtain viable cells per dish. The average of control cultures was considered 100%. Each value represents an average of at least six samples. The bar at each point is standard deviation. The bars not shown in figure were equal to sizes of symbol [1].

View larger version (21K): [in a new window]   Fig. 7. Neuroblastoma cells (50,000 per dish) were plated in tissue culture dishes (60 mm), and 5-fluorouracil (5-FU) (0.08 µg/mL) plus sodium ascorbate or sodium ascorbate alone was added 24 hours after plating. The drug and medium were changed every day, and the number of cells per dish was determined three days after treatment. Each value represents the mean of six to nine samples ± standard deviation [42].

View larger version (123K): [in a new window]   Fig. 8. Photomicrographs of neuroblastoma cells (NBP2) in culture after treatment with RO20-1724 and ß-carotene. Control cells (a) four days after plating (50,000 cells/60mm dish), showing mostly round cells; ß-carotene (20 µg/mL)-treated cells (b) four days after treatment showing no significant change in morphology; RO20-1724 (200 µg/mL)-treated cells (c) four days after treatment revealing increased number of cells with neurites; cells treated with RO20-1724 plus ß-carotene (d) for a period of four days showing more differentiated cells than those produced by RO20-1724 treatment alone; cells treated with RO20-1724 plus ß-carotene for a period of eight days (e) and (f) 11 days [55].

View larger version (113K): [in a new window]   Fig. 9. Photomicrographs of murine melanoma were taken four days after treatment. Control culture contained cells with varied morphology (a). The melanoma cells treated with vitamin E succinate (b) were elongated, had long cytoplasmic processes, and were arranged alongside each other. Melanoma cells treated with RO20-1724 (c) were large and elongated, had some long processes, and were arranged alongside each other. A combination of RO20-1724 and vitamin E succinate (d) increased the level of morphologic differentiation more than that produced by individual agents [56].

View larger version (25K): [in a new window]   Fig. 10. Effect of d--tocopheryl succinate (vitamin E succinate) in combination with sodium butyrate on the growth of neuroblastoma cells in culture. Cells (50,000 cells/60 mm dish) were plated in tissue culture dishes, and vitamin E succinate and sodium butyrate were added one after another 24 hours later. Fresh growth medium and agents were changed at two days after treatment and growth was determined at three days after treatment. Each value represents an average of six samples. The bar at each point is SEM [57].