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Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours
A V Patterson1, K J Williams, R L Cowen
1School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Abstract:
Overwhelming clinical and experimental data demonstrate that tumour hypoxia is associated with aggressive disease and poor treatment outcome as hypoxic cells are refractive to radiotherapy and some forms of chemotherapy. However, hypoxia is rare in physiologically normal tissues representing a tumour-specific condition. To selectively target this therapeutically refractive cell population, we have combined bioreductive chemotherapy with hypoxia-directed gene therapy. We have transfected the human fibrosarcoma cell line, HT1080, with a hypoxia-regulated expression vector encoding the human flavoprotein cytochrome c P450 reductase (HRE-P450R). This conferred hypoxia-dependent sensitivity to the alkylating nitroimidazole prodrug RSU1069 in vitro, with a greater than 30-fold increase in oxic/hypoxic cytotoxicity ratio compared with controls. Xenografts of both the HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to single dose radiotherapy of up to 15 Gy. However, combining a prodrug of RSU1069 with a reduced radiotherapy dose of 10 Gy represents a curative regimen (50% tumour-free survival; day 100) in the HRE-P450R xenografts. In complete contrast, 100% mortality was apparent by day 44 in the empty vector control xenografts treated in the same way. Thus, an oxygen-sensitive gene-directed enzyme prodrug therapy approach may have utility when incorporated into conventional radiotherapy and/or chemotherapy protocols for loco-regional disease in any tissue where hypoxia is a contra-indication to treatment success. doi:10.1038/sj.gt.3301702
Insights
Tumor hypoxia, a challenge in cancer treatment, was targeted using gene therapy. This approach enhanced chemotherapy effectiveness against hypoxic cells, leading to curative outcomes in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Tumor hypoxia is linked to aggressive cancers and poor treatment response.
- Hypoxic cells are resistant to radiation and chemotherapy.
- Hypoxia is a tumor-specific condition.
Purpose of the Study:
- To combine bioreductive chemotherapy with hypoxia-directed gene therapy.
- To selectively target and treat the therapeutically refractive hypoxic cell population.
Main Methods:
- Transfected HT1080 fibrosarcoma cells with a hypoxia-regulated expression vector encoding cytochrome P450 reductase (HRE-P450R).
- Assessed hypoxia-dependent sensitivity to the prodrug RSU1069 in vitro.
- Evaluated combination therapy in HRE-P450R and control xenografts.
Main Results:
- HRE-P450R transfectants showed significantly increased RSU1069 sensitivity in hypoxic conditions.
- Combination therapy (RSU1069 prodrug + reduced radiotherapy) achieved 50% tumor-free survival in HRE-P450R xenografts.
- Control xenografts showed 100% mortality under the same treatment conditions.
Conclusions:
- Oxygen-sensitive gene-directed enzyme prodrug therapy is a promising strategy.
- This approach can be integrated with conventional radiotherapy and chemotherapy.
- It offers potential for treating loco-regional disease where hypoxia impedes treatment success.