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Action of intermediate doses of methotrexate on dihydrofolate reductase in malignant diseases

F Tzortzatou-Stathopoulou1, H Zavitsa-Pateli, G Mousatos

  • 1First Department of Pediatrics, University of Athens, Aghia Sophia Children's Hospital, Greece.

Pediatric Hematology and Oncology
|January 1, 1987
PubMed

Insights

Intermediate methotrexate (MTX) doses partially inhibit dihydrofolate reductase (DHFR) in children with cancer, with effects most pronounced in specific white blood cells. Complete DHFR inhibition was not observed even with high MTX doses.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Methotrexate (MTX) is a chemotherapy agent that inhibits dihydrofolate reductase (DHFR).
  • Understanding MTX's in vivo effect on DHFR activity is crucial for optimizing cancer treatment protocols.
  • Previous studies using biochemical techniques suggested small MTX doses inhibit DHFR.

Purpose of the Study:

  • To investigate the in vivo effect of intermediate MTX doses on DHFR activity in leukocytes of pediatric cancer patients.
  • To compare cytochemical findings with previous biochemical studies on MTX-DHFR interactions.

Main Methods:

  • A cytochemical technique was employed to study DHFR activity in intact leukocytes from 16 children with malignant diseases.
  • Patients received weekly MTX doses ranging from 500 mg to 2 g/m2, followed by leucovorin rescue.
  • Enzyme activity was assessed within 24 hours post-MTX infusion.

Main Results:

  • Intermediate MTX doses partially inhibited DHFR activity in leukocytes.
  • Reduced DHFR activity was most evident in polymorphonuclear cells and monocytes.
  • Complete inhibition of DHFR activity was not achieved, even with the high MTX doses administered.

Conclusions:

  • Cytochemical analysis indicates that intermediate MTX doses achieve only partial DHFR inhibition in vivo.
  • Findings contrast with previous reports suggesting complete inhibition with smaller MTX doses.
  • Further studies using potentially higher MTX doses are warranted to explore the possibility of complete DHFR inhibition.

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