Parekh H K, Mansuri-Torshizi H, Srivastava T S, Chitnis M P
Chemotherapy Division, Tata Memorial Centre, Parel, Bombay, India.
Cancer Lett. 1992 Jan 10;61(2):147-56. doi: 10.1016/0304-3835(92)90173-s.
The effect of vitamin K3 (2-methyl-1,4-naphthoquinone) on Adriamycin (ADR) induced growth inhibition of drug sensitive and multidrug resistant P388 leukemia cells was evaluated. Exposure to ADR concentrations of 100-5000 ng simultaneously with 1 microM vitamin K3 elicited an enhanced inhibition of tumor cell survival. The effect of treatment with ADR alone, or in combination with vitamin K3 on DNA and RNA biosynthesis in the sensitive and resistant tumor cells, was also assessed. DNA and RNA biosynthesis inhibition was increased in P388/S (the parental cell line) and P388/ADR cells (the ADR resistant cell line which exhibits the multidrug resistant (MDR) phenotype) exposed to ADR after pretreatment for 3 h with vitamin K3. Concurrent administration in vivo of vitamin K3 and ADR illustrated a therapeutically significant increase (P less than 0.05) in the life span of sensitive and resistant tumor cell bearing animals. Vitamin K3 caused a depletion of the intracellular glutathione (GSH) levels in P388/S and P388/ADR leukemia cells but at concentrations greater than those that enhanced ADR cytotoxicity. Pretreatment of the tumor cells with 1 microM vitamin K3 induced a 35-50% (P less than 0.001) elevation in the intracellular ADR accumulation in MDR P388 leukemia cells, while such an effect was absent in P388/S tumor cells. DNA binding studies performed utilizing calf thymus DNA, indicated that vitamin K3 enhanced the intercalation potential of ADR and also altered the equilibrium between the free and bound form of ADR in a cell free system. These factors and their possible effects on the potentiation of ADR cytotoxicity and the therapeutic significance of utilizing vitamin K3 as an adjuvant in the chemotherapy of MDR tumors is discussed.
评估了维生素K3（2-甲基-1,4-萘醌）对阿霉素（ADR）诱导的药物敏感和多药耐药P388白血病细胞生长抑制的影响。与1 microM维生素K3同时暴露于100 - 5000 ng的ADR浓度下，可增强对肿瘤细胞存活的抑制作用。还评估了单独使用ADR或与维生素K3联合处理对敏感和耐药肿瘤细胞中DNA和RNA生物合成的影响。在用维生素K3预处理3小时后，暴露于ADR的P388/S（亲本细胞系）和P388/ADR细胞（表现出多药耐药（MDR）表型的ADR耐药细胞系）中，DNA和RNA生物合成抑制增加。维生素K3和ADR在体内同时给药表明，携带敏感和耐药肿瘤细胞的动物的寿命有治疗意义的显著增加（P小于0.05）。维生素K3导致P388/S和P388/ADR白血病细胞内谷胱甘肽（GSH）水平降低，但浓度高于增强ADR细胞毒性的浓度。用1 microM维生素K3预处理肿瘤细胞可使MDR P388白血病细胞内ADR积累增加35 - 50%（P小于0.001），而在P388/S肿瘤细胞中则没有这种作用。利用小牛胸腺DNA进行的DNA结合研究表明，维生素K3增强了ADR的嵌入潜力，并在无细胞系统中改变了ADR游离形式和结合形式之间的平衡。讨论了这些因素及其对增强ADR细胞毒性的可能影响，以及将维生素K3用作MDR肿瘤化疗辅助剂的治疗意义。
