Combining bioreductive drugs and radiation for the treatment of solid tumors*,**

https://doi.org/10.1053/srao.2003.50008Get rights and content

Abstract

Methods now exist for the identification of human tumors that contain significant numbers of hypoxic cells and are thereby suitable for treatment with bioreductive drugs to eliminate this refractory cell population. However, to fully exploit the potential of bioreductive drugs, they will need to be used in combination with other modalities likely to target the proliferating aerobic cells in the tumor. Radiation is the treatment that is most effective in killing aerobic cells; therefore, the present report reviews the available preclinical data on combined radiation/bioreductive drug treatments. Copyright 2003, Elsevier Science (USA). All rights reserved.

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Early concepts in the development of bioreductive drugs

The idea of bioreductive drug activation and the selective killing of hypoxic cells developed along 2 complimentary pathways. The first of these arose from observations made by Sutherland8 who noted that the hypoxic cell radiosensitizer, metronidazole, appeared to selectively kill the central hypoxic cells in multicellular spheroids. The second approach came from the recognition by Kennedy et al9 and Sartorelli10 that the presence of hypoxia in tumors created an environment conducive to

Bioreductive drugs used with radiation

The observations that hypoxic cell radiosensitizers could also function as hypoxic cell cytotoxins led to a more detailed evaluation of what contribution cytotoxicity could make to the outcome of radiosensitization experiments carried out in vivo. Conventionally, radiosensitizers such as metronidazole, misonidazole, etanidazole, and nimorazole are given to experimental mice before radiation because for sensitisation to occur drugs only need to be present in the hypoxic tumour cells at the

Future directions

Denny and colleagues3 first articulated the trigger/effecter concept in bioreductive drug development. Examples are given in Figures 3 and 4 in which the bioreductive prodrugs are putatively inactive until subjected to reductive metabolism under hypoxic conditions.

. Mechanism of the reductive elimination of aspirin from a 2-nitroimidazole prodrug.68.

. Mechanism of the reductive elimination of an alkylating mustard from an indolequinone prodrug.69.

Addition of a single electron will cause structural

Conclusions

The development of bioreductive drugs might be regarded as a mature science waiting for definitive, repeatable, clinical evidence that their use in combination with radiotherapy alone or chemo/radiotherapy will be of therapeutic benefit. However, the indicators are promising. There is firstly the positive interaction of TPZ combined with cisplatin in the treatment of non–small-cell lung cancer. Secondly, there are the positive clinical trials combining radiotherapy with MMC in the treatment of

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    *

    Supported by the Medical Research Council Grant Number G9520193.

    **

    Address reprint requests to Ian J. Stratford, PhD, School of Pharmacy and Pharmaceutical Sciences, University of Manchester Coupland III Building, Oxford Road, Manchester M13 9PL, UK.

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