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"text": "Table 2. Ribonucleotide Depletion in Human CEM Leukemic Cells Induced by Bullatacin (6) at 100 ng/mL [p6.4.1]",
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"text": "We had noted that bullatacin (6) was selectively cytotoxic for the A-2780 (human ovarian carcinoma) cell line in the NCI tumor panel, so at Upjohn xenografts of A-2780 were prepared and implanted into athymic mice. As a positive control, cisplatin, in a single dose of 5000 [p6.5.1]g/kg, caused, after 10 days, 78% tumor growth inhibition (TGI); bullatalicin (9) at 1000 [p6.5.2]g/kg/day for 10 days caused 75% tumor growth inhibition; bullatacin (6) at 50 [p6.5.3]g/kg/day caused 67% TGI; and the bullatacinones (5) at 125 [p6.5.4]g/kg/day caused 52% TGI.[p6.5.5] Subsequently, at Eli Lilly and Company (Indianapolis), the late Gerry Grindey showed that bullatacin (6) at 50 [p6.5.6]g/kg/day caused 66% TGI against X-5563 plasma cell myeloma implants in athymic mice; he also confirmed our observations that the acetogenins are extremely potent in their cytotoxic effects by determining that bullatacin (6) gave IC[p6.5.7] values of <10[p6.5.8] [p6.5.9]g/mL against human CCRF-CEM leukemic cells. Other companies tested our acetogenins, but, in our naive absence of formal testing agreements, some refused to inform us of the results.",
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"text": "demand for ATP. Not only is the hydrolysis of ATP needed to supply the biochemical energy required for cell division, but, as the key nucleotide, ATP is a basic building block of the nucleic acids that are needed for chromosomal construction for new mitochondria and new nuclei. Cancer cells must produce ATP as rapidly as possible, and any interruption of ATP production would be expected to upset the timing of cell division and have apoptotic consequences."
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"text": "It is now understood that the endogenous molecular biology of cancer cells involves the autocrine and paracrine secretion of insulin and insulin-like growth factors (IGF I and II), which facilitate the enhanced energy production and growth stimulation, respectively, required by these cells. A practical consequence of this is insulin-potentiated chemotherapy in which a small amount of insulin is coadministered with chemotherapeutic agents and causes, along with increased glucose uptake, a more rapid uptake of the agent into the cancer cells.[p6.12.1] Breast cancer cells, for example, have an average of 7 times more insulin receptors[p6.12.2] and 10 times more IGF receptors[p6.12.3] than normal breast cells. Thus, these cells can take up glucose 17 times faster than normal cells, and it is logical that they must be able to metabolize glucose 17 times faster than normal cells. The increased glucose in cancer cells must be metabolized, either aerobically (utilizing mitochondria and the NADH:oxidoreductase of complex I) or anaerobically (utilizing the NADH oxidase of the plasma membrane). Inhibitors of these enzymes would be expected to show a selection for cancer cells, and the resulting inhibition of glucose metabolism would deplete the levels of ATP and the related nucleotides, leading the cancer cell to apoptosis. Sophia Fotopoulos, at Clinical Reference Laboratory (Lenexa, KS), kindly determined for us the nucleotide levels in human CEM leukemic cells as they were being killed with bullatacin (6); after three days the levels of all of the ribonucleotides were decreased significantly just as one would expect (Table 2). Supporting this conclusion is the evidence for constituently high levels of NADH oxidase in cancer cells versus normal cells; the enzyme is markedly elevated in the plasma membrane vesicles of cancerous HeLa cells and HL-60 cells, but not in vesicles isolated from normal hepatocytes. [p6.12.4]",
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