Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methotrexate (MTX) acts by inducing cellular depletion of reduced folates, which ultimately leads to an inhibition of DNA synthesis. Like many anticancer drugs, this antimetabolite has little selectivity for tumor cells, and its effectiveness is limited by toxicity to normal tissues, particularly gastrointestinal epithelium and bone marrow. Previous studies have shown that MTX inhibits colony formation of the hematopoietic progenitor cells (CFU-C) in vitro. Whether this effect is due to a cytotoxic or a cytostatic mechanism has not been resolved. The present study was undertaken to eludicate the mechanism by which MTX inhibits CFU-C formation. Bone marrow cells in agarose cultures supplemented with recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF) were incubated for 7 days in the presence or absence of MTX. Exposure to 33 nM to 1 microM MTX reduced colony formation by more than 80% when compared to control cultures. When bone marrow suspension cultures supplemented with rmGM-CSF were incubated for 5 days in the presence or absence of MTX, exposure to 10 nM to 1 microM MTX resulted in a 60 to 80% reduction in cell numbers when compared to untreated cultures. Residual CFU-C numbers were determined in the same cultures by replating into agarose. Exposure to 10 nM MTX was found to enhance CFU-C recovery three-fold as compared to controls and cultures exposed to higher MTX concentrations. Addition of 10 microM of the reduced folate leucovorin (LV; 5-formyl-tetrahydrofolate) prevented CFU-C accumulation in the presence of 10 nM MTX. The kinetics of LV rescue of CFU-C, pre-exposed to 100 nM MTX, were investigated in clonogenic assays. The addition of 1 microM LV to semisolid bone marrow cultures preincubated with 100 nM MTX for up to 8 days completely abolished the inhibition of colony formation seen with 100 nM MTX alone. When the dose range of MTX was expanded from 33 nM to 3.3 microM, we found that administration of 10 microM LV on day 5 rescued the hematopoietic progenitors from MTX inhibition in all groups. These observations suggest that MTX is not cytotoxic to hematopoietic progenitors over its entire dose range but that it can induce a reversible block in the proliferation and differentiation of cells in the progenitor compartment.
 ...
PMID:Effect of methotrexate on murine bone marrow cells in vitro: evidence of a reversible antiproliferative action. 772 Aug 15

Patients with refractory malignant lymphoma (RML) have a poor prognosis when treated with conventional chemotherapy. The use of high-dose chemotherapy has been limited by secondary myelosuppression. We report the use of intensive and short-duration chemotherapy in patients with RML who received granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of hematological support and salvage with bone marrow transplantation or infusion of peripheral blood stem cells. Thirty-one patients with RML were treated with cyclophosphamide: 7 g/m2, iv on day 1, followed by GM-CSF: 5 micrograms/kg/day, subcutaneously until hematological recovery (granulocytes > 1.8 x 10(9)/L) started on day 2. Methotrexate, 5 g/m2, was also given when the granulocytes and platelets counts were normal, followed by leucovorin rescue. Epirubicin, 180 mg/m2, iv, was given on day 29 if the granulocyte count was normal, and GM-CSF was started on day 30. Complete response was obtained in 21 out of 31 patients (67%) and partial response in 4 more, thus an overall response was achieved in 80% of the treated patients. Time to treatment failure was 24+ months, and the overall survival was 28+ months. Hematological toxicity grade IV, according to the WHO criteria was observed in all cycles, however hematological recovery was already evident on day 13 +/- 2. Eleven patients developed infection related to the treatment, but no therapy related death was observed. GM-CSF was well tolerated with minimal toxicity. Is evident that GM-CSF can act as hematological support after high-dose chemotherapy in patients who cannot undergo bone marrow transplantation programs.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:GM-CSF instead of hematological support during high-dose chemotherapy for refractory malignant lymphoma. 858 Aug 3