BioWorld International Correspondent

LONDON - The drug imatinib (Gleevec), which is a highly specific treatment for chronic myelogenous leukemia, also may be able to cause regression of many different types of tumors, a new study suggests.

A team of researchers working in Germany showed that imatinib can induce a process known as cellular autophagy, in which the cell digests unwanted proteins and materials, and which sometimes ends in cell death.

Hermann Schatzl, professor of clinical virology at the Technical University of Munich, told BioWorld International: "This was not known before, and it was a very unexpected finding. We believe that this more general effect of imatinib may be true for many different types of tumors."

Schatzl, whose main interest is neurodegenerative diseases, said it now would be important for others to investigate the potential of imatinib to induce cellular autophagy in various tumor types.

The group published its work in the March 1, 2007, issue of Leukemia in a paper titled, "The anticancer drug imatinib induces cellular autophagy."

Justus Duyster, professor of internal medicine and hematology at the Technical University of Munich, who also is an author of the paper, told BioWorld International: "We plan to look at the bone marrow of patients taking imatinib to see whether there is evidence of autophagy in their cells. This finding could also be important for understanding the side effects of this drug, as it can induce myelosuppression."

In chronic myeloid leukemia, two genes called BCR and Abl are fused together by a chromosomal translocation. The resulting protein has a tyrosine kinase function, which is inhibited by imatinib. The drug also is used to treat gastrointestinal stromal tumors, where it is thought to inhibit a tyrosine kinase that drives the growth of that type of tumor.

"In these cases, imatinib is known to act in a highly specific way and stops cancer growth," Schatzl said. "But our results suggest that it also has a much broader effect, which might be beneficial for other types of tumors. Besides stopping further growth, autophagy might even result in some form of tumor regression."

Schatzl's interest in imatinib began when other researchers reported the drug could inhibit the production of beta-amyloid in a cell culture model of Alzheimer's disease, suggesting that it might be possible to develop imatinib as a new therapy for that condition.

His group subsequently showed that imatinib could induce clearance of the pathological form of prion protein from prion-infected cells, by activating degradation of the abnormal protein via the cells' lysosomes.

"When we found that imatinib helps cells to get rid of unwanted proteins, we wanted to know what the molecular mechanism was," Schatzl said. "We looked at many different types of cells, and we always found that the drug had this general effect by increasing the autophagy program."

Autophagy is a process by which the cell removes some constituents of the cytoplasm to the lysosomes. The first step is production of a double-membrane vesicle called the autophagosome, which engulfs part of the cytoplasm containing the unwanted material. The autophagosome then fuses with enzyme-containing lysosomes, and its contents are degraded and recycled.

Research has shown that autophagy may help a cell to adapt to some types of stress, such as infection with pathogens, and thus survive, or it may lead to cell death. Along with apoptosis and necrosis, therefore, autophagic provides a third route to cell death.

As Schatzl and his colleagues explained in Leukemia, the role of autophagy in cancer is still not completely understood. "It is not clear whether autophagy kills cancer cells or protects them from adverse conditions," they wrote.

Some studies suggested that there are lower than normal levels of autophagy in malignant tumors. For example, a single copy of a gene encoding a protein that is essential for induction of autophagy when cells are deprived of nitrogen is deleted in 40 percent to 75 percent of sporadic human breast, prostate and ovarian cancers. Introducing the gene back into cells that lacked it induced autophagy and inhibited cell proliferation.

In addition, researchers have shown that various established anticancer therapies - including, for example, tamoxifen, temozolomide and rapamycin - also induce autophagy or autophagic cell death.

There also is some evidence that autophagy can protect cancer cells and help them to survive.

It therefore will be important, the group emphasized, to determine in which cancer cells autophagy is induced following cancer therapy, and whether autophagy protects the cells by blocking the apoptotic pathway or kills them by leading to autophagic cell death.