Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells

摘要: Temozolomide (TMZ), an oral alkylating agent with good penetration of the blood-brain barrier, has shown efficacy in treatment malignant brain tumors. Ribonucleotide reductase (RR), rate-limiting enzyme DNA synthesis, seems to be a complementary target for combination chemotherapy Trimidox (TX) and didox (DX) are two recently synthesized specific inhibitors RR. The combinations TMZ TX or DX as basis synergistic protocols were tested this study. effects single drugs TMZ, DX, TX, TMZ/DX TMZ/TX evaluated human glioma cell lines U87MG, T98G, LNZ308, wt1119. In latter, experiments carried out presence absence wild-type p53 protein expressed under control tetracycline-responsive transgene system. Cytotoxicity was by MTT assays. isobologram index (CI) method Chou-Talalay used evaluate interactions between drugs. All demonstrated cytotoxicity tumor cells. Synergistic cytotoxic (CI<1) at different dose levels most examined lines. some instances, however, drug resulted additive even antagonistic effects. Toxicity agents synergy did not correlate expression toxicity may modified novel RR is synergistically enhanced cases. Depending on ratio, doses each given degree effect drastically reduced.