Rapamycin throws a Master switch. (Cancer).

Research on the potential anticancer drug rapamycin has revealed a possible new mechanism for suppressing large numbers of genes simultaneously, rather than each gene individually. Normally, genes are individually activated or inactivated by proteins targeted to the specific genes. But recent research led by principal investigator X. E Steven Zheng, an assistant professor of pathology at the School of Medicine of Washington University in St. Louis, Missouri, shows that a protein named "target of rapamycin," or TOR, acts on many different genes simultaneously, producing a stress response that can stop cancer cells from reproducing. The study is published in the December 2002 issue of Molecular Cell

Zheng and colleagues studied the molecular action of rapamycin, which currently is used to suppress the immune system after kidney transplant. The drug is derived from the soil bacterium Streptomyces hygroscopicus, native to the island of Rapa Nui (Easter Island). Rapamycin regulates a myriad of diverse cellular functions at the level of transcription and translation by inhibiting TOR. Clinical studies show that rapamycin also appears to both inhibit the formation of tumors and suppress tumor angiogenesis (the development of the blood vessels a tumor needs to obtain nutrients from its host), thus taking double-barreled aim at human cancers. These unique properties have led physicians to test its use as an anticancer drug.

In an approach known as "chemical genomics," Zheng and colleagues used rapamycin to inactivate TOR in yeast in a collection of mutant yeast strains, one for each gene in the yeast genome and each lacking one gene. This enabled them to measure how TOR interacts with each yeast gene, using rapamycin sensitivity (how much growth is inhibited by the drug) as a gauge.

Zheng and his team found about 300 yeast genes to be associated with TOR-related activities. The product of one such gene is a protein known as silent information regulator 3, or Sir3, which clings to the genes responsible for stress proteins, thereby inactivating them and keeping them silent. Sir3 appears to be the key to TOR's multigene activity: When rapamycin inactivated TOR, Sir3 molecules began detaching themselves from the chromatin regions carrying stress protein genes. This triggered a stress response; cells started producing stress proteins, their walls thickened, and they stopped proliferating. This is likely one of several mechanisms that contribute to shutting down cancerous cells. Michael McDaniel, a professor of pathology and immunology at the Washington University in St. Louis School of Medicine, calls it "a novel transcriptional mechanism that may further enhance the use of rapamycin as an anticancer agent."

Moreover, the researchers found that when rapamycin suppressed TOR, it also interrupted nutrient processing pathways, thereby preventing yeast cells from using glucose to produce energy and amino acids to make new proteins. Zheng and his team suggest that when rapamycin inhibits TOR, it works by eliciting a number 'of responses such as those of stress and starvation. Such responses are believed to cause cells to stop proliferating.

McDaniel notes that a key feature of rapamycin's overall mechanism of action--its ability to block cellular growth and proliferation--extends to normal, healthy cells as well as cancerous ones. He suggests that these potential adverse effects of rapamycin may be minimized by short-term use and the optimization of drug doses. He adds that Zheng's genomic study in yeast should provide a detailed map of the pathways by which the drug works, which will help in devising better therapeutic interventions for relevant human diseases.

The knowledge developed from the study of rapamycin's action needs to be verified in human cells, particularly tumor cells. If these results are borne out and the side effects are not intolerable, the result may be a new approach to causing malignant tumors to go into remission. If certain types of cancer are not fully cured, they might at least be upgraded from fatal diseases to manageable chronic diseases.