Chemotherapy of human malignant glioma: prevention of efficacy by dexamethasone?
Steroids are commonly administered for the control of edema, mass effect, and side effects from therapy to patients with malignant glioma who are receiving radiotherapy and chemotherapy. Here, we report that therapeutic concentrations of dexamethasone (DEX) attenuate cytotoxicity and growth inhibition of human malignant glioma cells induced by exposure to several chemotherapeutics, including ACNU, VM-26, vincristine, cytarabine, methotrexate, and adriamycin. DEX-mediated cytoprotection is not linked to DEX effects on glioma cell proliferation. However, the cytoprotective effects of DEX appeared to be more prominent in cell lines with wild-type p53 status (n = 2) than in p53 mutant cell lines (n = 3). Further, DEX-mediated rescue from chemotherapy does not directly involve Bcl-2 family proteins since DEX failed to change the expression of Bcl-2 or Bax proteins and since bcl-2 gene transfer-mediated cytoprotection was not redundant with the effects of DEX. DEX thus appears to control a common, bcl-2-independent death pathway in glioma cells that is not limited to specific drug actions. Chemotherapy is usually given as an elective, adjuvant treatment to glioma patients in stable condition who can tolerate steroid withdrawal. To maximize therapeutic efficacy, steroids should be withdrawn from glioma patients prior to chemotherapy.
Weller
M
M
Department of Neurology, University of Tübingen, Medical School, Germany.
Schmidt
C
C
Roth
W
W
Dichgans
J
J
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D005910:Glioma; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D015376:Nimustine / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013713:Teniposide / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003561:Cytarabine; D015376:Nimustine; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D013713:Teniposide; D008727:Methotrexate