Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells.
OBJECTIVE
Temozolomide (TMZ), an oral alkylating agent with good penetration of the blood-brain barrier, has shown efficacy in the treatment of malignant brain tumors. Ribonucleotide reductase (RR), the rate-limiting enzyme of DNA synthesis, seems to be a complementary target for combination chemotherapy of brain tumors. Trimidox (TX) and didox (DX) are two recently synthesized specific inhibitors of RR. The combinations of TMZ with TX or DX as a basis for synergistic chemotherapy protocols were tested in this study.


METHODS
The effects of the single drugs TMZ, DX, and TX, and the combinations TMZ/DX and TMZ/TX were evaluated in the human malignant glioma cell lines U87MG, T98G, LNZ308, and wt1119. In the latter, experiments were carried out in the presence or absence of wild-type p53 protein expressed under the control of a tetracycline-responsive transgene system. Cytotoxicity was evaluated by MTT assays. The isobologram and combination index (CI) method of Chou-Talalay were used to evaluate interactions between drugs.


RESULTS
All drugs demonstrated cytotoxicity in brain tumor cells. Synergistic cytotoxic effects (CI<1) for TMZ and TX or DX at different dose levels were demonstrated in most of the examined cell lines. In some instances, however, drug combinations resulted in additive or even antagonistic effects. Toxicity of the single agents and synergy of the combinations did not correlate with wild-type p53 expression in the tumor cells.


CONCLUSIONS
The tumor toxicity of TMZ as a single agent may be modified by combinations with the novel RR inhibitors DX and TX, and is synergistically enhanced in most cases. Depending on the combination ratio, the doses for each drug for a given degree of effect in the combination may be drastically reduced.
Figul
M
M
Department of Neurosurgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Söling
A
A
Dong
H J
HJ
Chou
T-C
TC
Rainov
N G
NG
D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000627:therapeutic use*; D001550:Benzamidines / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured / Q000187:drug effects
C074761:3,4,5-trihydroxybenzamidoxime; D018906:Antineoplastic Agents, Alkylating; D001550:Benzamidines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D003606:Dacarbazine; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid; D000077204:Temozolomide