Teicher B A, Holden S A, Rudolph M B, Sotomayor E A, Herman T S
Dana-Farber Cancer Institute, Boston, MA.
Int J Hyperthermia. 1991 Nov-Dec;7(6):905-15. doi: 10.3109/02656739109056458.
Bioflavonoids are known to inhibit enzymes in the glycolytic pathway and have been reported to decrease tumour blood flow. The antineoplastic capabilities of flavone acetic acid (FAA), dimethylaminoethyl-flavone-8-acetate (FAA ester) and quercitin (Q) as a function of pH, level of oxygenation and in conjunction with hyperthermia or SR-4233. In vitro, exposure of FSaIIC murine fibrosarcoma cells to various concentrations of FAA or FAA ester for 1 h demonstrated that both drugs were slightly more toxic toward hypoxic cells at 37 degrees C and pH 7.40 (but were somewhat less cytotoxic at pH 6.45 and 37 degrees C) than towards normally oxygenated cells. The cytotoxicity of FAA and FAA ester increased only minimally by concomitant treatment of cells at 42 degrees C or 43 degrees C. When temperatures of tumour-bearing mice anaesthetized with chloral hydrate and pentobarbital were measured both FAA (200 mg/kg) and Q (200 mg/kg) caused a more rapid drop in tumour versus core temperature, indicating a relative shutdown of tumour blood flow had been produced by these flavonoids. In Hoechst 33342 dye-defined subpopulations, both FAA and Q were only minimally cytotoxic in the subpopulation enriched in euoxic (bright) cells, producing surviving fractions of 0.70 and 0.29, respectively but were approximately 2-fold and 3-fold respectively more toxic towards the subpopulation enriched in hypoxic (dim) cells. When FAA preceded hyperthermia approximately a 3-4-fold increase in cell kill resulted from the combination in both subpopulations. Finally, when SR-4233, a selective hypoxic cell cytotoxic agent, was administered prior to FAA or Q and followed by hyperthermia the level of tumour cell killing increased so that the surviving fractions were 0.009 and 0.0055, respectively, in the dim cell subpopulation. These results indicate that FAA, FAA ester and Q may be most effectively used in a setting involving a combined modality regimen with a focus on the hypoxic tumour cell population.
已知生物类黄酮可抑制糖酵解途径中的酶，并且据报道能减少肿瘤血流量。研究了黄酮乙酸（FAA）、二甲基氨基乙基 - 黄酮 - 8 - 乙酸酯（FAA酯）和槲皮素（Q）在不同pH值、氧合水平下以及与热疗或SR - 4233联合使用时的抗肿瘤能力。在体外，将FSaIIC小鼠纤维肉瘤细胞暴露于不同浓度的FAA或FAA酯中1小时，结果表明，在37℃和pH 7.40时，这两种药物对缺氧细胞的毒性略高于正常氧合细胞（但在pH 6.45和37℃时细胞毒性略低）。同时在42℃或43℃处理细胞时，FAA和FAA酯的细胞毒性仅略有增加。在用氯水合醛和戊巴比妥麻醉的荷瘤小鼠体温测量中，FAA（200mg/kg）和Q（200mg/kg）均导致肿瘤温度相对于核心温度更快下降，表明这些类黄酮使肿瘤血流量相对减少。在经Hoechst 33342染料鉴定的亚群中，FAA和Q对富含常氧（明亮）细胞的亚群细胞毒性极小，存活分数分别为0.70和0.29，但对富含缺氧（暗淡）细胞的亚群毒性分别约高2倍和3倍。当FAA先于热疗时，两个亚群中联合使用导致细胞杀伤增加约3 - 4倍。最后，当在FAA或Q之前给予选择性缺氧细胞细胞毒性剂SR - 4233并随后进行热疗时，肿瘤细胞杀伤水平增加，使得在暗淡细胞亚群中的存活分数分别为0.009和0.0055。这些结果表明，FAA、FAA酯和Q可能最有效地用于以缺氧肿瘤细胞群体为重点的联合治疗方案中。
