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Biochemical interactions between methotrexate and 1-beta-D-arabinofuranosylcytosine in hematopoietic cells of children: a Pediatric Oncology Group study.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 1990; Vol. 27 (1), pp. 60-6. - Publication Year :
- 1990
-
Abstract
- Children with acute lymphocytic leukemia (ALL) in remission were treated with overlapping sequential infusions of methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (araC) as part of continuation therapy. The doses and the sequence were chosen to mimic conditions that produced greater than additive antineoplastic activity with these two drugs in preclinical studies. To assess the potential for the drug combination to exhibit greater than additive effect in vivo, we investigated several biochemical parameters that had been associated with synergism in vitro. Because the patients were in remission, the intracellular parameters could only be measured in cytologically normal hematopoietic cells. We observed that (1) the mean plasma concentrations of MTX and araC were above those required to obtain a greater than additive cytotoxicity with the two drugs in tissue culture; (2) MTX did not have a significant antipurine effect in bone marrow mononuclear cells; (3) the mean intracellular concentration of deoxycytidine triphosphate (dCTP) was significantly lower after treatment with the drug combination than after therapy with araC alone; and (4) the ratio of araC triphosphate (araCTP) to dCTP was 2.6 times higher after treatment with the combination than after araC alone. These results indicate that it is possible to achieve in patients the biochemical conditions associated with the greater than additive antineoplastic activity of MTX and araC in vitro.
- Subjects :
- Bone Marrow drug effects
Cells, Cultured drug effects
Child
Cytarabine administration & dosage
DNA, Neoplasm biosynthesis
Drug Evaluation
Drug Synergism
Hematopoietic Stem Cells metabolism
Humans
Leucovorin administration & dosage
Methotrexate administration & dosage
Precursor Cell Lymphoblastic Leukemia-Lymphoma blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Remission Induction
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Cytarabine pharmacology
Hematopoietic Stem Cells drug effects
Methotrexate pharmacology
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0344-5704
- Volume :
- 27
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 2245494
- Full Text :
- https://doi.org/10.1007/BF00689278