Cyclosporin A Reduces Anthracycline Resistance in Acute Myeloid Leukemia
Results recently published in the journal
Blood suggest that Cyclosporine A reduces resistance to anthracycline-based chemotherapy agents in patients with acute myeloid leukemia.
Acute myeloid leukemia (AML) is a cancer of the bone marrow and blood characterized by uncontrolled growth of immature white blood cells known as myelocytes. Although the use of new therapies has dramatically improved treatment of AML over the past 30 years, the majority of patients with this disease will still die within two years of diagnosis. Myelodysplastic syndrome refers to a group of conditions affecting the bone marrow which often develops into AML.
Anthracyclines are a group of chemotherapy agents widely used to induce remission in AML patients. Daunorubicin (DNR) is one of the most effective anthracyclines used in the treatment of AML. However, previous studies have found that some AML patients are resistant to anthracycline-based chemotherapy agents and that these patients have extremely poor survival rates. Patients resistant to anthracyclines have been found to have high levels of a type of protein called P-glycoprotein (Pgp) in the blood. Pgp expels chemotherapy agents from the inside of the cancer cell. Elevated levels of Pgp results in reduced levels of chemotherapy agents inside cells, effectively causing a resistance to those agents.
To overcome Pgp-induced anthracycline resistance, researchers are investigating agents that will impair the action of Pgp. In laboratory tests, researchers have found that Cyclosporine A (CsA) is a potent inhibitor of Pgp, resulting in higher levels of DNR within cells.
The Southwest Oncology Group enrolled 226 patients diagnosed with refractory AML (cancer progresses during treatment) or recurrent AML or myelodysplastic syndrome. Patients were divided into two groups: one group received the chemotherapy agents cytarabine and DNR and the other group received CsA in addition to cytarabine and DNR.
Two years following therapy, 34% of patients who received CsA were still cancer free compared to only 9% of patients who did not receive CsA. In addition, overall survival was significantly higher in patients who received CsA (22% versus 12%). The greatest effect was seen in patients exhibiting moderate to high levels of Pgp.
There was no difference in treatment-related deaths between the patients treated with or without CsA. There was also no difference in the severity or frequency of stomatitis (inflammation or ulcers of the gastrointestinal tract) or renal toxicity (kidney failure). Patients taking CsA did experience more nausea than other patients and they also experienced more severe hyperbilirubinemia (elevated levels of bilirubin). However, in both cases, these side effects appeared to be transient, did not cause severe toxicity and were reversible once treatment ended.
The addition of CsA to anthracycline-based chemotherapy regimens reduces resistance to DNR, prolongs duration of remission and improves overall survival for AML patients. Individuals with AML may wish to speak with their physician regarding the risks and benefits of including CsA in chemotherapy treatment or about participating in a clinical trial. Two sources of information regarding ongoing clinical trials include comprehensive, easy-to-use listing services provided by the National Cancer Institute (
eCancerTrials.com. eCancerTrials.com also provides personalized clinical trial searches on behalf of patients. (
Blood, Vol 98, No 12, pp 3212-3220, 2001)
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