Design of Novel Bioreductive Drugs
There is currently a great need and indeed considerable enthusiasm to search for new drug molecules with improved therapeutic selectivity in the major solid tumours. One approach is to screen novel structures for activity in biologically relevant models. This is the new approach taken by the United States National Cancer Institute which places much emphasis on panels of human cell lines to test natural products in vitro. An alternative strategy is to identify differences in biochemical structure and function between normal and neoplastic cells and to develop agents to exploit these novel targets on a rational basis. There are many new and exciting possibilities. The elaboration of agents which interfere with oncogene function, growth factors and their receptors, transmembrane signal transduction and so on, are good examples. Considerable attention is also being directed towards another exploitable target based on the aberrant physiology of solid tumours: cellular hypoxia .
KeywordsOncol Melphalan NADH Breccia Metronidazole
Unable to display preview. Download preview PDF.
- 3.Hall EH: Radiobiology for the Radiologist. Harper and Row, New York 1988Google Scholar
- 7.Wasserman TH, Sieman D and Workman P (eds): The Seventh International Conference on Chemical Modifiers of Cancer Treatment. Int J Radiat Oncol Biol Phys 1992 (22, Nos. 3 and 4):391–825Google Scholar
- 14.Jenkins TC, Naylor MA, O’Neill P, Threadgill MD, Cole S, Stratford U, Adams GE, Fielden EM, Suto MJ and Stier MA: Synthesis and evaluation 1 -[3-(2-haloethylamino)propyl)-2-nitroimidazoles as prodrugs of RSU 1069 and its analogs, which are radiosensitizers and bioreductively activated cytotoxins. J Med Chem 1990 (33):2603–2610PubMedCrossRefGoogle Scholar
- 23.Binger M and Workman P: Pharmacokinetic contribution to the improved therapeutic selectivity of a novel bromoethylamino prodrug (RB 6145) of the mixed-function hypoxic cell sensitizer/cytotoxin alpha-(1 -aziridinomethyl)-2-nitro-1 H-imidazole-1 -ethanol (RSU 1069). Cancer Chemother Pharmacol 1991 (29):37–47PubMedCrossRefGoogle Scholar
- 26.Workman P and Walton MI: Enzyme-directed bioreductive drug development. In: Adams GE, Breccia A, Fielden EM, Wardman P (eds) Selective Activation of Drugs by Redox Processes. Plenum Press, New York 1991 pp 173–191Google Scholar
- 28.Workman P, Walton MI, Wolf CR, Hemingway S and Riley RJ: Cytochrome P450s and cytochrome P450 reductase are the major enzymes in the reduction of the bioreductive SR 4233 (WIN 59075) by mouse liver microsomes. Proc Am Assoc Cancer Res 1992 (33):526Google Scholar
- 36.Workman P, Walton MI, Bibby MC and Double JA: In vitro response of mouse adenocarcinoma of the colon (MAC) tumours to indoloquinone E09: correlation with bioreductive enzyme content. Br J Cancer 1990 (62):215Google Scholar
- 39.Hoban PR, Walton MI, Robson CN, Godden J, Stratford U, Workman P, Harris AL and Hickson ID:Decreased NADPH: cytochrome P-450 reductase activity and impaired drug activation in a mammalian cell line resistant to mitomycin C under aerobic but not hypoxic conditions. Cancer Res 1990 (50):4692–4697PubMedGoogle Scholar
- 46.Leliveld P, Double JA, Bibby MC, Stratford IJ and Moody CJ: Antitumour activity and bioreductive potential of the mitosene GBJ 584. Annal Oncol 1992(3, Suppl 1):101Google Scholar
- 47.Patterson LH, Maine JE, Cairns DC, Craven MR, Bennett N, Fisher GR, Ruparelia K and Giles Y: Use of N-oxides of DNA affinic anthraquinones as bioreductive prodrugs. Annal Oncol 1992 (3, Suppl 1):94Google Scholar