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. 1994 Dec;70(6):1067–1074. doi: 10.1038/bjc.1994.450

DNA-targeted 2-nitroimidazoles: in vitro and in vivo studies.

D S Cowan 1, J F Matejovic 1, R A McClelland 1, A M Rauth 1
PMCID: PMC2033674  PMID: 7981056

Abstract

A series of compounds in which a 2-nitroimidazole is linked to a DNA intercalating phenanthridine moiety has been synthesised. Previously, three such compounds, termed nitroimidazole-linked phenanthridines or NLPs, were tested in vitro and showed a greatly enhanced molar efficiency as hypoxic cell radiosensitisers and cytotoxins compared with the untargeted 2-nitroimidazole, misonidazole. Since the cytoxicity of these compounds was shown to be inversely proportional to linker chain length while radiosensitising ability was dependent of it, compounds with five and six carbons in the chain were synthesised in an attempt to lower the toxicity of the drugs while increasing their ability to 'scan' DNA for target radicals. These compounds and a comparison series of n-alkylated phenathridinium ions have been characterised and evaluated in vitro using Chinese hamster ovary and V79 cells and their effects compared with misonidazole. Based on in vitro results, one member of the series was selected and evaluated in vitro using a V79 spheroid tumour model and in vivo using an SCCVII transplantable tumour system. These studies have demonstrated the potential utility of this class of compound.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams G. E., Ahmed I., Clarke E. D., O'Neill P., Parrick J., Stratford I. J., Wallace R. G., Wardman P., Watts M. E. Structure-activity relationships in the development of hypoxic cell radiosensitizers. III. Effects of basic substituents in nitroimidazole sidechains. Int J Radiat Biol Relat Stud Phys Chem Med. 1980 Dec;38(6):613–626. doi: 10.1080/09553008014551451. [DOI] [PubMed] [Google Scholar]
  2. Adams G. E., O'Neill P., Ahmed I., Stratford I. J., Fielden E. M. The development of some nitroimidazoles as hypoxic cell sensitizers. Cancer Clin Trials. 1980 Spring;3(1):37–42. [PubMed] [Google Scholar]
  3. Brown J. M. Clinical trials of radiosensitizers: what should we expect? Int J Radiat Oncol Biol Phys. 1984 Mar;10(3):425–429. doi: 10.1016/0360-3016(84)90063-4. [DOI] [PubMed] [Google Scholar]
  4. Brown J. M., Workman P. Partition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole. Radiat Res. 1980 Apr;82(1):171–190. [PubMed] [Google Scholar]
  5. Cowan D. S., Kanagasabapathy V. M., McClelland R. A., Rauth A. M. Mechanistic studies of enhanced in vitro radiosensitization and hypoxic cell cytotoxicity by targeting radiosensitizers to DNA via intercalation. Int J Radiat Oncol Biol Phys. 1992;22(3):541–544. doi: 10.1016/0360-3016(92)90871-e. [DOI] [PubMed] [Google Scholar]
  6. Cowan D. S., Panicucci R., McClelland R. A., Rauth A. M. Targeting radiosensitizers to DNA by attachment of an intercalating group: nitroimidazole-linked phenanthridines. Radiat Res. 1991 Jul;127(1):81–89. [PubMed] [Google Scholar]
  7. Denny W. A., Roberts P. B., Anderson R. F., Brown J. M., Phil D., Wilson W. R. NLA-1: a 2-nitroimidazole radiosensitizer targeted to DNA by intercalation. Int J Radiat Oncol Biol Phys. 1992;22(3):553–556. doi: 10.1016/0360-3016(92)90874-h. [DOI] [PubMed] [Google Scholar]
  8. Morgan A. R., Lee J. S., Pulleyblank D. E., Murray N. L., Evans D. H. Review: ethidium fluorescence assays. Part 1. Physicochemical studies. Nucleic Acids Res. 1979 Oct 10;7(3):547–569. doi: 10.1093/nar/7.3.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Panicucci R., Heal R., Laderoute K., Cowan D., McClelland R. A., Rauth A. M. NLP-1: a DNA intercalating hypoxic cell radiosensitizer and cytotoxin. Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):1039–1043. doi: 10.1016/0360-3016(89)90911-5. [DOI] [PubMed] [Google Scholar]
  10. Roberts P. B., Denny W. A., Wakelin L. P., Anderson R. F., Wilson W. R. Radiosensitization of mammalian cells in vitro by nitroacridines. Radiat Res. 1990 Aug;123(2):153–164. [PubMed] [Google Scholar]
  11. Siemann D. W., Hill R. P., Bush R. S. The importance of the pre-irradiation breathing times of oxygen and carbogen (5% CO2: 95% O2) on the in vivo radiation response of a murine sarcoma. Int J Radiat Oncol Biol Phys. 1977 Sep-Oct;2(9-10):903–911. doi: 10.1016/0360-3016(77)90188-2. [DOI] [PubMed] [Google Scholar]
  12. Smith P. J., Anderson C. O. Modification of the radiation sensitivity of human tumour cells by a bis-benzimidazole derivative. Int J Radiat Biol Relat Stud Phys Chem Med. 1984 Oct;46(4):331–344. doi: 10.1080/09553008414551511. [DOI] [PubMed] [Google Scholar]
  13. THOMLINSON R. H., GRAY L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955 Dec;9(4):539–549. doi: 10.1038/bjc.1955.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Tannock I. F. Oxygen diffusion and the distribution of cellular radiosensitivity in tumours. Br J Radiol. 1972 Jul;45(535):515–524. doi: 10.1259/0007-1285-45-535-515. [DOI] [PubMed] [Google Scholar]
  15. Weinberg M. J., Lapointe T. A., Rauth A. M. Growth delay in a murine squamous cell tumor after local radiation and concurrent infusional 5-fluorouracil treatment. Int J Radiat Oncol Biol Phys. 1986 Aug;12(8):1449–1452. doi: 10.1016/0360-3016(86)90192-6. [DOI] [PubMed] [Google Scholar]

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