The Japanese experiences with hypoxia-targeting pharmacoradiotherapy: from hypoxic cell sensitisers to radiation-activated prodrugs

Abstract

Tumour hypoxia is a negative factor in cancer radiotherapy. In order to overcome the problem, various pharmacotherapies have been investigated as an adjunct to radiotherapy. The use of hypoxic cell sensitisers is a classical strategy, and many new compounds have been developed and investigated. Development of more efficient compounds than those currently available seems difficult and clinical studies to prove the efficacy of the existing compounds are encouraged, especially in combination with radiosurgery, intraoperative radiotherapy, and interstitial irradiation, in which a single high dose of radiation is used. Following the advent of hypoxic cell sensitisers, hypoxic cytotoxins have become available. Among them, tirapazamine has already gained success when combined with cisplatin in non-small cell lung cancer. The beneficial effect of tirapazamine when combined with radiation needs to be determined. As a third-generation compound in this field, antitumour prodrugs that are activated by irradiation under hypoxic conditions via one-electron reduction have been proposed. Prodrugs of 5-fluorouracil and 5-fluoro-2’-deoxyuridine have shown in vivo as well as in vitro activity. Although clinical evaluation of the compounds is not warranted due to a relatively low in vivo effect, this strategy appears promising if the prodrug design can be applied to more potent agents that shall be developed in future.