Exploiting tumour hypoxia in cancer treatment

Key Points

  • 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.

Abstract

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.

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Figure 1: The vascular network of normal tissue versus tumour tissue.
Figure 2: The usual mechanism by which prodrugs act as hypoxia-selective cytotoxins.
Figure 3: The mechanism by which tirapazamine selectively kills hypoxic cells.
Figure 4: Mechanisms of activation under hypoxia of prodrugs.
Figure 5: Rationale for hypoxia-dependent gene therapy.
Figure 6: Clostridial-dependent enzyme prodrug therapy—simulation of how it might work.

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Acknowledgements

The authors work is funded by grants from the United States National Institutes of Health (J.M.B. and W.R.W.) and the Health Research Council of New Zealand (W.R.W.).

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Correspondence to J. Martin Brown.

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Competing interests

J. Martin Brown has a research grant from Sanofi-Synthelabo, the company that owns tirapazamine.

J. Martin Brown and William R. Wilson have equity (<5%) in a company, Proacta Therapeutics Ltd., formed to exploit hypoxia in cancer treatment.

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DATABASES

Cancer.gov

head and neck cancer

non-small-cell lung cancer

oesophageal cancer

ovarian cancer

Entrez Gene

CYP3A4

ERBB2

HIF-1α

HIF-1β

P450R

p53

SRC

Glossary

HYPOXIA

A low oxygen level. However, this means different levels to different investigators depending on the phenomenon being investigated. For the radiation biologist, hypoxia occurs at levels that produce severe radiation resistance or levels less than 0.1% O2 in the gas phase. Other effects of hypoxia occur at oxygen levels above and below this value.

P-GLYCOPROTEIN

A protein localized to the cell membrane that actively pumps many drugs out of the cell. High levels of this protein lead to resistance to many anticancer drugs.

PRODRUG

A latent form of a drug that can be activated by metabolism or other chemical transformation in the body.

TOPOISOMERASE II

An enzyme that catalyses changes in DNA topology by transiently cleaving and re-ligating both strands of the double helix. This enzyme catalyses the passage of one DNA double-stranded molecule through another.

ELECTROPHILE

A chemical group that reacts with electron-rich centres in molecules.

FREE RADICAL

A compound with an unpaired electron and that is usually very reactive because of this feature.

BYSTANDER EFFECT

Influence of a drug on untargeted cells, in the present context by diffusion of an activated cytotoxin from hypoxic cells to surrounding cells at higher oxygen concentrations.

NITROGEN MUSTARD

DNA-crosslinking alkylating agents containing a bis(X-ethyl)amine group, where X is an electrophile that can react with nucleophiles such as the N7 position of guanine.

GDEPT

(Gene-directed enzyme prodrug therapy). A cancer treatment strategy that aims to deliver a prodrug-activating enzyme specifically to tumour cells using gene therapy. The anticancer effect would be achieved by subsequent systemic administration of the non-toxic prodrug, which would be converted to a toxic drug preferentially in the tumour cells.

CDEPT

(Clostridial-dependent enzyme prodrug therapy). A cancer therapy using the non-pathogenic species of the obligate anaerobe genus clostridia that have been genetically engineered to express a prodrug-activating enzyme. This is used to activate a prodrug within the hypoxic/necrotic regions that are colononized by the bacterium.

ADEPT

(Antibody-directed enzyme prodrug therapy). A cancer treatment strategy that involves conjugation of a prodrug-activating enzyme (such as cytosine deaminase, which converts the non-toxic prodrug 5-fluorocytosine to the anticancer drug 5-fluorouracil) to a tumour-targeting antibody.

VASCULAR-TARGETING AGENT

Drugs that damage existing blood vessels and therefore interfere with blood flow in tumours.

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Brown, J., Wilson, W. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4, 437–447 (2004). https://doi.org/10.1038/nrc1367

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