Despite the increase in cure rate of childhood ALL from 4 per cent to more than 80 per cent during the past 40 years the cause of failure in the remaining 20 per cent of children is largely unknown. The current findings could help to further reduce the number of failures.
William Evans, senior author of this study told DrugResearcher.com: "Our results provide the first genomic insight into why some patients leukemia cells are resistant to individual medications and others are not. This is pointing others and us to new targets for the development of new agents to convert drug-resistant ALL to drug-sensitive ALL."
"We think this is pointing us to potential avenues for curing the remaining 20 per cent of patients who are not cured with current therapy."
The researchers identified four groups of genes, each with characteristic expression patterns in leukemia cells depending on sensitivity or resistance to the anti-cancer drugs, prednisolone, Oncovin (vincristine), Elspar (L-asparaginase) and Systemic (daunorubicin). Investigators found the expression patterns of these genes were related to treatment outcome.
In addition, 123 previously unrecognised genes associated with resistance to cancer chemotherapy were identified. Only three of these genes had been previously linked to drug resistance.
Evans explained: "It shows that an unbiased approach to discover genes associated with drug resistance can identify many new genes that have not been previously linked to drug resistance."
"121 of 124 genes identified were completely unexpected and never previously linked to cancer drug resistance."
Crucially, the researchers found no universal cross-resistance gene that would block sensitivity to all four drugs. Genes linked to resistance belonged to different functional categories (i.e. they did different tasks in the cell) and these differed for each medication.
The study further supports the practice of combination anti-cancer drug therapy to treat ALL. Combination therapy uses multiple anti-cancer drugs to attack different biochemical functions simultaneously.
Evans added: "We are placing all of our primary data in the public domain, as we wish for anyone interested to have access, toward exploiting it for developing new medications."
Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. In the United States, about 3,000 children each year are found to have ALL. It affects lymphocytes, a type of white blood cell. Leukemic cells accumulate in the bone marrow, replacing normal blood cells and spreading to other organs.
Chemotherapy is used to kill leukemia cells. All chemotherapy is stopped after two to three years of treatment. Hematopoietic stem cell transplantation is an option for very high-risk cases.
The findings are published in the August 4, 2004 issue of the New England Journal of Medicine (NEJM).