Jachez B, Nordmann R, Loor F
Sandoz Pharma Ltd., Preclinical Research, Basel, Switzerland.
J Natl Cancer Inst. 1993 Mar 17;85(6):478-83. doi: 10.1093/jnci/85.6.478.
Taxol, a promising agent for the treatment of cancer, has entered phase II clinical trials. Nevertheless, it belongs to the class of compounds that show impaired retention in multidrug-resistant cells expressing P-glycoprotein (Pgp), a drug efflux pump. Chemosensitizers like verapamil modulate multidrug resistance by interfering with the efflux action of Pgp and thus can decrease drug resistance or can restore drug sensitivity by restoring normal drug accumulation and distribution within the multidrug-resistant tumor cell. The two strongest, nearly equipotent chemosensitizers identified to date are the cyclosporine derivative SDZ PSC 833 and the semisynthetic cyclopeptolide SDZ 280-446.
This study was designed to investigate the capacities of verapamil, SDZ PSC 833, and SDZ 280-446 to decrease resistance of two multidrug-resistant cell lines to taxol.
We studied in vitro the growth of two multidrug-resistant tumor cell lines displaying high resistance to taxol: multidrug-resistant Chinese hamster ovary cells and murine monocytic leukemia P388 cells. We determined the taxol concentration that produced 50% inhibition of cell growth (IC50) in the two multidrug-resistant cell lines and in the parent cell lines, in the presence of a range of chemosensitizer concentrations (0-30 microM). IC50 values were determined in the presence and in the absence of verapamil, SDZ PSC 833, or SDZ 280-446.
At nontoxic concentrations (0.3-1 microM), SDZ PSC 833 and SDZ 280-446 produced an almost complete reversal of the high taxol resistance of the multidrug-resistant tumor cells, whereas only partial restoration of sensitivity to taxol was achieved with verapamil.
SDZ PSC 833 and SDZ 280-446 can restore the normal taxol sensitivity of highly resistant multidrug-resistant tumor cells.
The combination of taxol with SDZ PSC 833 or SDZ 280-446 may be recommended for treatment of multidrug-resistant cancers.
紫杉醇是一种很有前景的抗癌药物，已进入II期临床试验。然而，它属于在表达P-糖蛋白（Pgp，一种药物外排泵）的多药耐药细胞中滞留受损的化合物类别。像维拉帕米这样的化学增敏剂通过干扰Pgp的外排作用来调节多药耐药性，从而可以降低耐药性，或者通过恢复多药耐药肿瘤细胞内正常的药物积累和分布来恢复药物敏感性。迄今为止确定的两种最强且几乎等效的化学增敏剂是环孢素衍生物SDZ PSC 833和半合成环肽内酯SDZ 280 - 446。
本研究旨在调查维拉帕米、SDZ PSC 833和SDZ 280 - 446降低两种多药耐药细胞系对紫杉醇耐药性的能力。
我们在体外研究了两种对紫杉醇高度耐药的多药耐药肿瘤细胞系的生长：多药耐药的中国仓鼠卵巢细胞和小鼠单核细胞白血病P388细胞。我们在一系列化学增敏剂浓度（0 - 30微摩尔）存在的情况下，测定了在两种多药耐药细胞系及其亲本细胞系中产生50%细胞生长抑制（IC50）的紫杉醇浓度。IC50值是在有和没有维拉帕米、SDZ PSC 833或SDZ 280 - 446的情况下测定的。
在无毒浓度（0.3 - 1微摩尔）下，SDZ PSC 833和SDZ 280 - 446几乎完全逆转了多药耐药肿瘤细胞对紫杉醇的高度耐药性，而维拉帕米仅部分恢复了对紫杉醇的敏感性。
SDZ PSC 833和SDZ 280 - 446可以恢复高度耐药的多药耐药肿瘤细胞对紫杉醇的正常敏感性。
紫杉醇与SDZ PSC 833或SDZ 280 - 446联合使用可能推荐用于治疗多药耐药癌症。
