Perspectives of hypoxia in anticancer treatments: Activated prodrugs and bioreductive perfusions

Tumour hypoxia is a limiting factor in both the radiotherapy and chemotherapy of solid tumours. Paradoxically it is also an attractive therapeutic target, because significant hypoxia occurs only in solid tumours. Hypoxic cells can be considered for therapy by non-toxic, hypoxia-activated prodrugs. Conceptually, "trigger" units in these drugs are selectively activated in hypoxic cells to release or activate a toxic "effector", capable of killing surrounding oxygenated tumour cells. Useful triggers include quinones, nitroaromatics, N-oxides, and transition metals. At present the N-oxide tirapazamine (TPZ) is in phase HI clinical trials. Solid tumour tissue is poorly perfused compared with normal tissue. Reasons include a rather limited, poorly structured, and inefficient tumour vascular supply, and high interstitial pressures. This leads to variable delivery of oxygen, other nutrients and drugs, resulting in regions of hypoxia (oxygen partial pressures of <5-10 mm Hg) in many human solid tumours. This hypoxia can be classified into three broad types: a) chronic or diffusion hypoxia keeps cells, that are sufficiently distant from the nearest blood capillary, hypoxic for long periods; b) transient or perfusion hypoxia results from the temporary shutdown of blood vessels, placing areas of tissue under hypoxia for shorter periods; and c) acute hypoxia caused by blocking the blood flow by means of vasodilatative drugs, tourniquet and embolization or endovascular catheter ballons.