1. SUMMARY ..................................................... 5
2. AIMS ........................................................ 7
3. AVEMAR ..................................................... 11
3.1 Introduction .......................................... 11
3.2 Composition ........................................... 11
3.3 Safety ................................................ 12
3.4 Drug interactions ..................................... 12
3.4.1 Vitamin С ...................................... 13
3.4.2 Cytostatic Drugs ............................... 13
3.4.3 Tamoxifen ...................................... 14
3.5 Molecular targets of Avemar ........................... 14
3.5.1 PARP ........................................... 14
3.5.2 Pentose Phosphate Pathway ...................... 15
3.5.3 Ribonucleotide Reductase ....................... 16
3.5.4 Cyclooxygenases ................................ 17
4. HEAVY WATER (D2O) .......................................... 21
4.1 Introduction .......................................... 21
4.2 Physical Properties ................................... 21
4.3 History ............................................... 21
4.4 Effect on biological systems .......................... 22
4.5 Effect on animals and tumor cells ..................... 22
4.6 Toxicity in humans .................................... 24
5. GALLIC ACID ................................................ 27
6. PICEATANNOL ................................................ 31
7. RESVERATROL ................................................ 37
7.1 Introduction .......................................... 37
7.2 Cancer prevention by resveratrol ...................... 38
7.3 Antioxidant and cardioprotective effects of
resveratrol ........................................... 40
7.4 Pharmacokinetics ...................................... 42
7.5 Resveratrol analogs ................................... 44
8. MATERIALS AND METHODS ...................................... 58
8.1 Chemicals and supplies ................................ 58
8.2 Cell culture .......................................... 59
8.2.1 Devices ........................................ 59
8.2.2 Containers ..................................... 60
8.2.3 Cell culture media and supplements ............. 60
8.2.4 Cell lines ..................................... 60
8.3 Growth inhibition assay ............................... 61
8.4 Growth recovery assay ................................. 61
8.5 Hoechst dye 33258 and propidium iodide double
staining .............................................. 61
8.6 Cell cycle distribution analysis ...................... 62
8.7 Determination of deoxyribonucleoside triphosphates .... 62
8.8 Incorporation of 14C-labelled cytidine into DNA ....... 63
8.9 Enzyme immunoassay for activated nuclear NF-кВ
measurement ........................................... 63
8.10 Cyclooxygenase (COX) Inhibitor Screening Assay ........ 63
8.11 Statistical calculations .............................. 63
9. DISCUSSION ................................................. 65
10. SCIENTIFIC PUBLICATIONS .................................... 74
10.1 Research articles related to this thesis .............. 74
10.2 Poster presentations related to this thesis ........... 75
10.3 Complete list of research and review articles ......... 76
11. APPENDIX: ORIGINAL PUBLICATIONS ............................ 83
11.1 Avemar, a nontoxic fermented wheat germ extract,
induces apoptosis and inhibits ribonucleotide
reductase in human HL-60 promyelocytic leukemia
cells ................................................. 84
11.2 N-hydroxy-N'-(3,4,5-trimethoxyphenyl)-3,4,5-
trimethoxy-benzamidine, a novel resveratrol analog,
inhibits ribonucleotide reductase in HL-60 human
promyelocytic leukemia cells: synergistic antitumor
activity with arabinofuranosylcytosine ................ 96
11.3 Synthesis and cytotoxic activity of
resveratrol-based compounds .......................... 112
11.4 Biochemical effects of piceatannol on human HL-60
promyelocytic leukemia cells -synergism with Ara-C ... 119
11.5 Synergistic effects of Deuterium Oxide and
Gemcitabine in human pancreatic cancer cell lines .... 135
11.6 Antioxidant activity of resveratrol, piceatannol
and 3,3',4,4',5,5'-hexahydroxy-trans-stilbene in
three leukemia cell lines ............................ 150
11.7 Cytotoxic and Biochemical Effects of 3,3',4,4',5,5'-
hexahydroxystilbene, a Novel Resveratrol Analogue
in HL-60 Human Promyelocytic Leukemia Cells .......... 166
11.8 Gallic acid inhibits*ribonucleotide reductase and
cyclooxygenases in human HL-60 promyelocytic
leukemia cells ....................................... 184
11.9 Effects of heavy water (D2O) on human pancreatic
tumor cells .......................................... 197
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