Hirose M, Takeda E, Kuroda Y
Blood Transfuion Division, School of Medicine, University of Tokushima.
Jpn J Clin Oncol. 1993 Aug;23(4):232-7.
Mechanisms of the discrepant effect of methotrexate and dipyridamole on human hematologic cultured cell lines were investigated by analyzing intracellular methotrexate levels and thymidine incorporation through the salvage pathway, since the combination of methotrexate and dipyridamole has different effects according to cell type: additive effects on ML-1 and THP-1 (myelo-monocytoid cells); reduced effects on MOLT-3, SKW-3, P32/ish and BL-TH (lymphoid cells). Dipyridamole reduced the toxicity of methotrexate by diminishing intracellular methotrexate levels in MOLT-3 and BL-TH (lymphoid cells), in which the reduction of intracellular methotrexate affected more than just the blocking of the salvage pathway required for growth by dipyridamole. On the other hand, dipyridamole enhanced the toxicity of the combination by blocking the salvage pathway in an ML-1 (myelo-monocytoid cell) and in a methotrexate-resistant subline of BL-TH/MTX (lymphoid cell), in which the salvage pathways were considered activated. Dipyridamole could prove to be a useful drug for reversing the drug resistance caused by the activation of the salvage pathway.
通过分析细胞内甲氨蝶呤水平以及通过补救途径的胸苷掺入情况，研究了甲氨蝶呤和双嘧达莫对人血液学培养细胞系产生不同作用的机制。因为甲氨蝶呤和双嘧达莫的联合作用根据细胞类型而有所不同：对ML-1和THP-1（骨髓单核细胞）有相加作用；对MOLT-3、SKW-3、P32/ish和BL-TH（淋巴细胞）作用减弱。双嘧达莫通过降低MOLT-3和BL-TH（淋巴细胞）中的细胞内甲氨蝶呤水平来降低甲氨蝶呤的毒性，其中细胞内甲氨蝶呤的降低不仅影响了双嘧达莫对生长所需补救途径的阻断。另一方面，双嘧达莫通过阻断ML-1（骨髓单核细胞）和BL-TH/MTX（淋巴细胞）的甲氨蝶呤耐药亚系中的补救途径来增强联合用药的毒性，在这些细胞系中补救途径被认为是激活的。双嘧达莫可能被证明是一种用于逆转由补救途径激活引起的耐药性的有用药物。
