targeting hypoxia

[john]

Tirapazamine is being used in clinical trials

City of Hope is one center.

http://www.clinicaltrials.gov/ct/show/N ... 10?order=1

EXPLOITING TUMOUR HYPOXIA IN CANCER TREATMENT

J. Martin Brown & William R. Wilson about the authors

Preface

Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis. The cells in these hypoxic regions are resistant to both radiotherapy and chemotherapy. However, the existence of hypoxia and necrosis also provides an opportunity for tumour-selective therapy, including prodrugs activated by hypoxia, hypoxia-specific gene therapy, targeting the hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria. These strategies could turn what is now an impediment into a significant advantage for cancer therapy.

Summary

A characteristic feature of solid tumours is the presence of cells at very low oxygen tensions. These hypoxic cells confer radiotherapy and chemotherapy resistance to the tumours, as well as selecting for a more malignant phenotype.

These hypoxic cells, however, provide a tumour-specific targeting strategy for therapy, and four approaches are being investigated: prodrugs activated by hypoxia; hypoxia-selective gene therapy; targeting the hypoxia-inducible factor 1 (HIF-1) transcription factor; and the use of recombinant obligate anaerobic bacteria.

Tirapazamine is the prototype hypoxia-activated prodrug. Its toxic metabolite, a highly reactive radical that is present at higher concentrations under hypoxia, selectively kills the resistant hypoxic cells in tumours. This makes the tumours much more sensitive to treatment with conventional chemotherapy and radiotherapy.

Several other hypoxia-activated prodrugs, including AQ4N, NLCQ-1 and dinitrobenzamide mustards, are in preclinical or early clinical development.

Hypoxia-activated gene therapy using hypoxia-specific promoters provides selective transcription of enzymes that can convert prodrugs into toxic drugs. The efficacy of this approach has been shown in animal models, but clinical testing must await better systemic delivery of vectors to hypoxic cells.

Targeting HIF-1 is a third strategy. This protein is stabilized under hypoxic conditions and promotes the survival of tumour cells under hypoxic conditions. Several strategies to inactivate or to exploit this unique protein in tumours are being investigated at the preclinical level.

Finally, using recombinant non-pathogenic clostridia — an obligate anaerobe that colonizes tumour necrosis after systemic administration — is another strategy to exploit the unique physiology of solid tumours. This approach has demonstrated considerable preclinical efficacy.