Parekh H K, Shallom J M, Advani S H, Chitnis M P
Cancer Research Institute, Tata Memorial Centre, Parel, Bombay, India.
Neoplasma. 1991;38(6):575-81.
The ability of bepridil, a calcium channel blocker, to potentiate the antitumor activity of mitoxantrone (MITO) in human chronic myeloid leukemia (CML) cells was evaluated. MITO and bepridil, when incubated alone with the CML cells for 4 h, indicated a dose-dependent increase in the inhibition of 3H-thymidine incorporation. Incorporation rate of the radiolabeled thymidine into DNA was used as a measure of cell growth. When the CML cells were exposed to MITO (1 microgram/ml) in the presence of bepridil (1 and 5 micrograms/ml), an enhancement in the inhibition of DNA biosynthesis was observed in 14 out of 17 human CML samples studied. This significant inhibition (p less than 0.001) of 3H-thymidine incorporation due to the combination was found to be completely irreversible. Bepridil was identified predominantly in the octanol phase in the octanol/water partitioning studies. This lipophilic property of drug response modulators was implicated in the observed increase in the intracellular uptake of anticancer drugs, which in turn led to an enhanced cytotoxicity correlating well with the MITO activity observed in this study. The results are suggestive of clinical utility of bepridil as an adjuvant to enhance the anticancer ability of MITO in the treatment of CML.
评估了钙通道阻滞剂苄普地尔增强米托蒽醌（MITO）对人慢性粒细胞白血病（CML）细胞抗肿瘤活性的能力。将MITO和苄普地尔分别与CML细胞单独孵育4小时后，发现3H-胸腺嘧啶核苷掺入的抑制作用呈剂量依赖性增加。将放射性标记的胸腺嘧啶核苷掺入DNA的速率用作细胞生长的指标。当在苄普地尔（1和5微克/毫升）存在的情况下，将CML细胞暴露于MITO（1微克/毫升）时，在所研究的17个人CML样本中的14个中观察到DNA生物合成抑制作用增强。发现由于联合使用导致的3H-胸腺嘧啶核苷掺入的这种显著抑制（p小于0.001）是完全不可逆的。在正辛醇/水分配研究中，苄普地尔主要存在于正辛醇相中。药物反应调节剂的这种亲脂性与观察到的抗癌药物细胞内摄取增加有关，这反过来又导致细胞毒性增强，与本研究中观察到的MITO活性密切相关。结果提示苄普地尔作为辅助药物增强MITO在CML治疗中的抗癌能力具有临床应用价值。
