This is one of a trilogy of applications with a common theme. They concern the synthesis, testing in vitro and in vivo and the evaluation of mechanisms of action, of a generation of bio-reductive anti-cancer drugs that can function as hypoxic cell radiation sensitizers, as differential cytotoxic agents for oxygen-deficient cells in tumours and as potentiators of other anti-cancer drugs. These compounds are based on the principles of 'dual function' shown by the lead compound RSU 1069, a 2-nitroimidazole containing an aziridine function in the 1-substituted side chain. This compound gives rise to substantial radiation- and chemo-sensitization at doses an order of magnitude less than those required for misonidazole. Further, the differential toxicity towards hypoxic cells is extremely high showing the potential of this class of compound for use as anti-cancer drugs activated bio-reductively. The basic rationale for this collaborative programme is to synthesize new compounds of this type, examine their effectiveness as radiation sensitizers, chemo-sensitizers and differential cytotoxic agents for oxygen-deficient cells in a variety of cell lines in culture, in multi-cellular spheroids and in experimental tumours of different types that are already established in the applicants' laboratories. In addition, mechanistic studies will include investigation of structure activity relationships since it has already been shown that chemical modifications of RSU 1069 and similar types of compounds can profoundly affect cytotoxicity both in vitro and in vivo without greatly influencing sensitizing ability. For RSU 1069, the high differential hypoxic cytotoxicity is due to its conversion to a highly reactive bifunctional agent by anaerobic reduction. This leads to an increase in strand breakage and cross-linking in DNA. However, RSU 1069 which is also considerably more toxic than misonidazole to aerobic cells, causes oncogenic transformation in unirradiated C3H 10T 1/2 and balb 3T3 cells. An important part of the combined programme will be to examine therefore the transforming ability of the new compounds in a structure-activity study. This will be aimed at assessing the importance of factors such as electron-affinity, the degree of activation of the aziridinyl group and other mono-functional alkylating moieties, lipophilic properties and relationships, if any, between transforming ability, aerobic and hypoxic cytotoxicity and radiation-sensitizing effectiveness.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044126-02
Application #
3186681
Study Section
Radiation Study Section (RAD)
Project Start
1987-06-15
Project End
1990-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Medical Research Council
Department
Type
DUNS #
City
London
State
Country
United Kingdom
Zip Code
Naylor, M A; Threadgill, M D; Webb, P et al. (1992) 2-Nitroimidazole dual-function bioreductive drugs: studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives. J Med Chem 35:3573-8
Fielden, E M; Adams, G E; Cole, S et al. (1992) Assessment of a range of novel nitro-aromatic radiosensitizers and bioreductive drugs. Int J Radiat Oncol Biol Phys 22:707-11
Adams, G E; Stratford, I J; Edwards, H S et al. (1992) Bioreductive drugs as post-irradiation sensitizers: comparison of dual function agents with SR 4233 and the mitomycin C analogue EO9. Int J Radiat Oncol Biol Phys 22:717-20
Threadgill, M D; Webb, P; O'Neill, P et al. (1991) Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins. J Med Chem 34:2112-20
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Bremner, J C; Stratford, I J; Bowler, J et al. (1990) Bioreductive drugs and the selective induction of tumour hypoxia. Br J Cancer 61:717-21
Keohane, A; Godden, J; Stratford, I J et al. (1990) The effects of three bioreductive drugs (mitomycin C, RSU-1069 and SR4233) on cell lines selected for their sensitivity to mitomycin C or ionising radiation. Br J Cancer 61:722-6
Cobb, L M; Nolan, J; Butler, S A (1990) Distribution of pimonidazole and RSU 1069 in tumour and normal tissues. Br J Cancer 62:915-8
Jenkins, T C; Stratford, I J; Stephens, M A (1989) 3-Nitro-1,2,4-triazoles as hypoxia-selective agents. Anticancer Drug Des 4:145-60
Stratford, I J; Hickson, I D; Robson, C N et al. (1989) Radiosensitizing and cytotoxic effects of nitroimidazoles in CHO cells expressing elevated levels of glutathione-S-transferase. Int J Radiat Oncol Biol Phys 16:1307-10

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