Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells Journal Article
| Authors: | Figul, M.; Söling, A.; Dong, H. J.; Chou, T. C.; Rainov, N. G. |
| Article Title: | Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells |
| Abstract: | Purpose: 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. Conclusion: 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. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; cancer combination chemotherapy; dose response; drug potentiation; gemcitabine; cytarabine; temozolomide; brain tumor; glioma; brain neoplasms; dna synthesis; dacarbazine; bone marrow suppression; cancer cell culture; cytotoxicity; tumor cells, cultured; protein p53; drug synergism; enzyme inhibitors; glioblastoma; antineoplastic agents, alkylating; hydroxamic acids; 3,4 dihydroxybenzohydroxamic acid; ribonucleotide reductase; humans; human; priority journal; article; ribonucleotide reductases; didox; trimidox; 3,4,5 trihydroxybenzohydroxamidoxime; oxidoreductase inhibitor; benzamidines |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 52 |
| Issue: | 1 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2003-07-01 |
| Start Page: | 41 |
| End Page: | 46 |
| Language: | English |
| DOI: | 10.1007/s00280-003-0611-2 |
| PUBMED: | 12690517 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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