A Study of the Mechanisms of Intrinsic and Acquired Methotrexate Resistance in Acute Lymphocytic Leukemia
- Determine the mechanisms of intrinsic and acquired methotrexate resistance using in
vitro assays of matched initial diagnosis, relapsed, and nonrelapsed (control) leukemic
blast samples from patients with acute lymphoblastic leukemia in relapse or remission.
- Determine if the mechanisms of acquired methotrexate resistance are related to dosage
or timing of methotrexate administration or other clinical factors in these patients.
OUTLINE: Random samples of frozen leukemic blasts from relapsing patients at initial
diagnosis and relapse are selected. A corresponding sample from nonrelapsing patients
(control) at initial diagnosis is also randomly selected.
Reduced folate carrier (RFC) and dehydrofolate reductase (DHFR) expression is measured using
a quantitative reverse transcriptase-polymerase chain reaction assay of prepared RNA. DHFR
gene amplification is measured by a dot blot analysis of prepared DNA. Results of these
assays are used to determine if a particular mechanism of acquired methotrexate resistance
is associated with a particular subset of acute lymphoblastic leukemia patients. Data are
collected regarding the actual timing and dosage of methotrexate received by each patient
and are correlated with the mechanisms of resistance.
PROJECTED ACCRUAL: A total of 135 paired samples will be accrued for this study.
Mechanisms of intrinsic and acquired methotrexate resistance
Richard Gorlick, MD
Children's Hospital at Montefiore
United States: Federal Government