Role of p16 and p14ARF in radio- and chemosensitivity of malignant gliomas.
In addition to cytoreductive surgery, most patients with malignant gliomas also undergo radio- and chemotherapy. An improved understanding of the molecular genetic mechanisms underlying the radio- and chemosensitivity of gliomas may help to identify glioma patients who will benefit from aggressive and, therefore, potentially toxic adjuvant treatment. It may also allow for the development of new therapies aimed at improving the response of these tumors towards chemo- and radiotherapy. The INK4a gene products, p16 and p14ARF, have been suggested as potential regulators of glioma chemo- and radiosensitivity. We have used tetracycline controlled expression of p16 and plasmid-based p14ARF expression to study the chemo- and radiosensitivity of glioma cell lines. Ectopic p16 sensitized U-87MG cells towards treatment with vincristine and possibly also BCNU by approximately 1.5 to 2-fold, and towards ionizing radiation by a factor of 1.5. p14ARF expression was found to render U-87MG cells 2-fold more radioresistant than controls. These findings support a role for p16 and p14ARF as modulators of the radio-and chemosensitivity of gliomas. Further studies of the role of cell cycle regulators in glioma chemo- and radio-sensitivity seem warranted. We would like to point out that such candidate genes which may code for potent growth suppressors (like p16) or even toxic gene products can be successfully investigated using the approach detailed in this manuscript.
Simon
Matthias
M
Neurochirurgische Universitätsklinik, D-53105 Bonn, Germany. matthias.simon@ukb.uni-bonn.de
Voss
David
D
Park-Simon
Tjoung-Won
TW
Mahlberg
Ralph
R
Köster
Gertraud
G
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D016147:Genes, Tumor Suppressor; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism / Q000502:physiology*; D014750:Vincristine / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D014750:Vincristine; D002330:Carmustine