Researchers have engineered enediynes, a family of potent bioactive compounds, to enhance their anticancer activity (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0708274104). Some enediynes kill cancer cells by a dual mechanism: They cause breaks in double-stranded DNA, a reaction that requires molecular oxygen, and they create cross-links between DNA strands, a process that can occur under hypoxic conditions. The interiors of solid tumors, which are often hypoxic, don't respond well to enediynes that predominantly induce DNA breakage. In the new work, a group led by Ben Shen of the University of Wisconsin, Madison, and Terry A. Beerman of Roswell Park Cancer Institute, Buffalo, has found that enediynes modified with simple substitutions act predominantly by cross-linking. Irving Goldberg of Harvard Medical School comments that the modified enediynes might prove to be therapeutically advantageous, especially in solid tumors, and could help lead to a deeper understanding of the enediynes' dual mechanism.