Merry S, Hamilton T G, Flanigan P, Freshney R I, Kaye S B
Imperial Laboratories Ltd., Andover, Hampshire, U.K.
Eur J Cancer. 1991;27(1):31-4. doi: 10.1016/0277-5379(91)90054-h.
The development of pleiotropic drug resistance (PDR) in vivo in solid tumour models suggests that a similar process may occur in the clinic. A subline of the Ridgway osteogenic sarcoma (ROS)--a murine subcutaneously-growing solid tumour--with moderate resistance (1.5 fold) to actinomycin D was selected by repeated suboptimal treatment with this drug in vivo. This subline (ROS/ADX/G2) showed cross-resistance to vincristine (3.5 fold) and etoposide (over 5.1 fold) but not to doxorubicin. The resistance could in all cases be partly or completely overcome by treatment with non-cytotoxic doses of verapamil or clomipramine. Resistance to actinomycin in this model was associated with lower (up to 3.2 fold) drug accumulation into tumours which could be increased (up to 2.8 fold) by treatment with 25 micrograms/g verapamil. These data support clinical trials of the use of membrane-active agents to overcome PDR.
实体瘤模型中体内多药耐药性（PDR）的发展表明，临床上可能会发生类似过程。通过在体内反复用亚最佳剂量的放线菌素D处理，从Ridgway骨肉瘤（ROS）——一种小鼠皮下生长的实体瘤——中筛选出了对放线菌素D具有中度耐药性（1.5倍）的亚系。该亚系（ROS/ADX/G2）对长春新碱（3.5倍）和依托泊苷（超过5.1倍）表现出交叉耐药性，但对多柔比星无交叉耐药性。在所有情况下，用非细胞毒性剂量的维拉帕米或氯米帕明治疗可部分或完全克服耐药性。该模型中对放线菌素的耐药性与肿瘤内药物蓄积降低（高达3.2倍）有关，用25微克/克维拉帕米治疗可使药物蓄积增加（高达2.8倍）。这些数据支持使用膜活性药物克服PDR的临床试验。
