Hypoxic areas of tumours, and particularly of metastases, are notoriously resistant to chemo- or radiotherapies. Jiwu Wei et al. have developed a scheme to specifically deliver a cytotoxic gene product to hypoxic lung metastases, through embryonic endothelial progenitor cells (EPCs) that usually contribute to tumour vasculogenesis.

EPCs arise in the bone marrow and are recruited to sites of active neovasculogenesis by vascular endothelial growth factor (VEGF) and other factors. As they have been shown to contribute to the growing tumour vasculature, Wei et al. investigated if they could be used to deliver therapeutics to hypoxic tumours. They specifically chose to use EPCs isolated from mouse embryos, rather than adult EPCs, because they can be easily grown in culture and genetically manipulated. Also, as embryonic EPCs do not express major histocompatibility complex class I molecules, they are not rejected by the host's immune system.

Wei et al. showed that when these cells were injected into the tail veins of mice, they localized primarily to lung metastases that developed from transplanted osteosarcomas or Lewis lung carcinomas, but were also found in liver and kidney metastases. The EPCs homed mostly to poorly vascularized metastases, which were found to be hypoxic and expressed high levels of VEGF. So could these EPCs be used to deliver a cytotoxic 'suicide' gene to these metastases? The authors stably transfected EPCs with the yeast cytosine deaminase gene, fused to uracil phosphoribosyl transferase. This fusion enzyme converts the prodrug f-fluorcytosine (5-FC) into the cytotoxic compound 5-fluorouracil (5-FU), which can diffuse into the interstitial space and mediate a cytotoxic effect on surrounding tumour cells.

Wei et al. found that mice with established multiple lung metastases lived significantly longer after treatment with suicide-gene-harbouring EPCs and 5-FC, compared with controls. Up to 90% of all lung metastases were targeted by the cells, and the treatment was not found to cause any toxic effects or embryonic tumours. The mice, however, eventually succumbed to metastases formed in other organs, as well as the non-hypoxic, well-vascularized metastases that were not efficiently infiltrated by the EPCs. Another complication of the system was that it did not kill tumour cells immediately — it required time for the EPCs to incorporate into the tumour vasculature, to express the suicide gene and to kill bystander cells. Furthermore, control EPCs that did not carry the suicide gene actually promoted tumour vascularization and growth. Therefore, one crucial aspect for future clinical use will be the inclusion of safeguards to ensure that the cytotoxic system becomes activated in all EPCs.