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Effects of arsenic on human cells

A mechanism that may account for paradoxical effects of arsenic, which is both a treatment for cancer and a carcinogen has been discovered. The findings have implications for development of therapies for treating cancer and for health issues relating to acceptable levels of arsenic in drinking water.

RESEARCHERS AT Johns Hopkins have reported discovering a mechanism that may account for the paradoxical effects of arsenic, which is both a treatment for cancer and a carcinogen. Once a crucial element in the medical repertoire of Hippocrates for successfully treating infections like malaria and syphilis arsenic is also an effective treatment for certain types of leukaemia, or cancer of white blood cells.

Long-term exposure to arsenic in drinking water, however, has been linked to cancer of the bladder, lungs, skin, kidney, nasal passages, liver and prostate. "Arsenic has dual effects; in normal cells it can cause cancer, and in cancerous cells it can lead to cell death. We have found one mechanism that may explain both of these effects," says Chi V. Dang, professor and director of haematology at Hopkins. Specifically the team found that arsenic inhibits transcription of a gene, which in turn inhibits the expression of telomerase, an enzyme that protects the ends of chromosomes. Low levels of telomerase cause end-to-end fusions of chromosomes, which promote genetic instability.

This instability may then lead to cancer in healthy cells and apoptosis, or cell death, in cancerous cells, according to Dang. The Hopkins researchers report their findings in The Journal of Clinical Investigation.

While investigating how cancer cells react to arsenic, one of the researchers, Wen-Chien Chou, a graduate student in human genetics and molecular biology at Hopkins, noticed that some of the cells were abnormally large and tended to die sooner than expected. They then found that these big cells also had end-to-end fusion of their chromosomes, suggesting that arsenic was somehow causing genetic instability. "It didn't take long to put two and two together," says Dang.

"Once we saw the fused chromosomes we knew that telomerase might be responsible. So we did a direct experiment that asked: Does arsenic inhibit telomerase? The answer is yes. Cells exposed to arsenic exhibit a dramatic inhibition of telomerase.

"The findings have implications for both the development of therapies for treating cancer and for larger public health issues relating to acceptable levels of arsenic in drinking water. "We've provided evidence that arsenic causes genetic instability potentially leading to cancer," says Dang. "This provides an underlying scientific reason for why we don't want high levels of arsenic in our drinking water." The World Health Organization (WHO), the Department of Health and Human Services (DHHS), and the EPA have determined that arsenic is carcinogenic to humans. The results could also lead to development of more effective chemotherapy to treat leukaemia.

Studies in China and elsewhere have shown that arsenic trioxide is effective in treating acute promyelocytic leukaemia (APL), a variant of acute myeloid leukaemia that accounts for 10-15 percent of this cancer in adults, according to Dang. "Chemotherapy works by attacking different weak points of a cancer cell," says Dang.

"Our findings put into perspective how arsenic can be used in combination with other drugs in chemotherapy to fight cancer. "Arsenic naturally occurs throughout the earth's crust, water, air, plants and animals. It is released into the environment due to volcanism, erosion of rocks, forest fires, and also human industrial activity.

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