DNA topoisomerase I drugs and radiotherapy for lung cancer

Abstract

Lung cancer represents the most common cause of cancer-related mortality in the United States and around the world. DNA topoisomerase I (TOP1) drugs such as irinotecan and topotecan represent a unique class of chemotherapeutic agents that exhibit not only potent cytotoxic effect, but also tumor-selective radiation-sensitizing effect. The mechanism of cytotoxicity and radiation sensitization by TOP1 drugs has been intensely investigated. Modern radiotherapy, aided by improved imaging and treatment delivery technology, is capable of targeting tumors more precisely, while sparing surrounding critical structures. Clinical trials with camptothecin derivatives and radiotherapy have been conducted in lung cancers. Combined modality therapy with TOP1 drugs and radiotherapy offers a new frontier for lung cancer therapy. We review the present state of TOP1-targeted chemotherapy and modern radiotherapy for lung cancer.

Keywords: DNA topoisomerase I (TOP1); camptothecin derivative; lung cancer; radiation sensitizer; radiation therapy.

Figure 1

Chemical structures of camptothecin, topotecan and irinotecan.

Figure 2

A model for TOP1-mediated cytotoxicity and radiation sensitization. In this model, the drug-trapped TOP1 cleavable complex initiates TOP1-mediated DNA damage by “interacting” with replication fork during DNA synthesis. Double strand DNA breaks, replication fork arrest and an aborted “cleaved” TOP1-DNA complex can be generated. Based on the dependence on NHEJ double-strand DNA repair, current data indicate dissociation between the pathways lead to TOP1-mediated cytotoxicity and TOP1-mediated radiation.