Swiss Federal Institute of Technology, Lausanne

A chemist highlights promising organometallic drugs.

Traditionally, the compounds we use to fight cancer come in two flavours. Inorganic drugs, such as cisplatin — a small molecule with a platinum core — are the workhorses of chemotherapy. They are generally highly toxic to cells, not particularly selective, and are accompanied by side effects ranging from vomiting to kidney damage. Larger organic drugs offer a more targeted but weaker approach. They can selectively pick off key enzymes, but may work on only a narrow range of cancers.

In the search for more effective anticancer weaponry, hybrids of inorganic and organic components — organometallic drugs — are increasingly important. Once thought of as unstable, highly toxic species, these compounds are now being developed by chemists to treat a broad range of tumours and to overcome platinum-resistant cancer cells. Like organic drugs, they have a selective mode of action and so cause fewer side effects.

The dinuclear ruthenium-arene compounds trialled by Bernhard Keppler of the University of Vienna and his colleagues are promising examples (M. G. Mendoza-Ferri et al. J. Med. Chem. 52, 916–925; 2009). These highly cytotoxic compounds contain two ruthenium centres, separated by an adjustable organic linker. By tweaking the length of this chain, the researchers produced compounds that are as active as established platinum-based drugs in human tumour-cell lines.

What’s more, the ruthenium drugs could kill tumour cells that were resistant to oxoplatin, a drug related to cisplatin. They work by linking DNA duplexes together, and can also bind histone proteins to DNA.

The compounds have now progressed to experiments in animals. By reducing side effects, I hope the drugs can improve the quality of life for patients undergoing chemotherapy.

Harvard Medical School

A geneticist views two theories of X-chromosome inactivation in a broad context.

Female mammals have two X chromosomes, one of which is inactivated to ensure that females get the same dose of X-linked genes as males. Two long, non-coding RNA molecules mediate this process. One, Xist, initiates silencing of the chromosome to be inactivated, whereas its antisense partner, Tsix, blocks such silencing of the remaining X. The exact mechanism by which Xist and Tsix exert their functions is not known.

RNA interference (RNAi) describes a process by which RNA fragments ‘interfere’ with the creation of proteins from their RNA recipes. The recent discovery of RNAi in mammalian cells made it tempting to postulate that sense and antisense non-coding RNA partners, such as Xist and Tsix, are processed by the RNAi-associated enzyme DICER into small RNAs. Jeannie Lee and her team at Harvard Medical School have presented several lines of evidence in support of this, including data that demonstrate improper X inactivation in DICER’s absence (Y. Ogawa et al. Science 320, 1336–1341; 2008).

By contrast, a study by David Livingston of Harvard’s Dana-Farber Cancer Institute and his colleagues has shown that, in the absence of DICER, the inactive X chromosome in stem cells remains coated with Xist and several other repressive markers (C. Kanellopoulou et al. Proc. Natl Acad. Sci. USA 106, 1122–1127; 2009). This group suggests that the effects observed by Ogawa et al. may have been indirect because DICER is also involved in the processing of a class of small, non-coding RNAs known as microRNAs that can alter gene expression by fine-tuning protein production.

Despite their differences, these studies should provide an incentive to further investigate the potential role of the RNAi pathway in the nucleus of mammalian cells. This will shed light on both X inactivation and gene regulation in general.