In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin.
In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin.
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DOI：
10.1038/bjc.1997.154
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发表时间：
1997
影响因子：
8.8
通讯作者：
Sehested, M
中科院分区：
文献类型：
--
作者：
Jensen, PB;Holm, B;Sorensen, M;Christensen, IJ;Sehested, M
关键词：
获得耐药肿瘤细胞是一系列恶性疾病医疗中的主要问题。近年来，三类新的抗癌药物被提出进行临床试验，每种药物都有新的作用机制。这些是拓扑异构酶I(TOPO I)毒药拓扑替康和伊立替康，它们都是喜树碱的衍生物，紫杉烷微管蛋白稳定剂紫杉醇和紫杉醇，最后是抗代谢药物吉西他滨，它在实体肿瘤中很活跃。在与已有药物的结合中优化它们的使用是非常复杂的过程，有许多可能的药物和时间表方案。在这里，我们描述了一组广泛的耐药小细胞肺癌(SCLC)细胞系如何被用作肿瘤异质性的模型，以帮助选择非交叉耐药方案。我们从一个经典的(NCI-H69)和一个变异的(OC-NYH)小细胞肺癌细胞系中选择了低倍数(3-10倍)耐药亚系。耐药细胞系包括对烷化剂具有不同表型的两个亚系(H69/BCNU和NYH/CIS)、对Topo I类毒物具有不同表型的两个亚系(NYH/CAM和NYH/TPT)和三个多药耐药(MDR)亚系(H69/DAU、NYH/Vm和H69/VP)，这些细胞系结合了MDR1和MRP的高表达以及拓扑异构酶II(Topo II)的下调或突变。用一种标准化的克隆形成试验测定对20种已有药物和新药物的敏感性。耐药性具有高度的药物特异性。因此，没有一种细胞系对所有药物都具有抗药性。事实上，所有耐药细胞系都表现出对各种不同类别药物的侧枝敏感模式。最耐人寻味的模式是两个细胞系对吉西他滨的副作用敏感，五个耐药细胞系对阿糖胞苷敏感，即除对Topo I毒药耐药的系外的所有系。接下来，通过相关分析比较了9种细胞系中的所有敏感性模式。对于给定的一对化合物，高相关系数(CC)表明该组细胞系中的反应模式相似。这些数据证实了药物之间存在交叉耐药的观点。数值较低的系数表明两种药物的作用方式不同，表明两种药物之间缺乏交叉耐药性，负相关系数表明两种药物表现出侧支敏感性。对新药先导最阴性的CCS(%)依次为：紫杉醇-卡莫司汀(-75)、紫杉醇-顺铂(-58)、阿糖胞苷(-25)、吉西他滨-阿霉素(-32)、喜树碱-VM26(-41)和拓扑替康-VP16(-17)。与临床重要药物VP-16的相关性最大的是：顺铂(-70)；顺铂(-68)；喜树碱(-38)；博莱霉素(-33)、吉西他滨(-32)；阿糖胞苷(-21)；拓扑替康(-17)；马法兰(-3)；与其他主要药物顺铂的相关性依次为：阿霉素(-70)；VP-16(-70)；VM-26(-69)；阿莫沙星(-)；泰索帝(-58)；紫杉醇(-58)。紫杉醇和紫杉醇对VP-16高度相关(交叉耐药)(分别为0.76和0.81)，与顺铂呈负相关(均为-0.58)。同样，喜树碱和拓扑替康与顺铂相关，但与VP-16和其他Topo II毒药呈负相关。根据敏感性数据，我们得出结论，侧支敏感性和缺乏交叉耐药性有利于顺铂-紫杉烷或Topo I-Topo II毒药组合，而交叉耐药模式表明表鬼臼毒素-紫杉烷或Topo I毒物-顺铂组合可能不利。
The acquisition of drug-resistant tumour cells is the main problem in the medical treatment of a range of malignant diseases. In recent years, three new classes of anti-cancer agents, each with a novel mechanism of action, have been brought forward to clinical trials. These are the topoisomerase I (topo I) poisons topotecan and irinotecan, which are both camptothecin derivatives, the taxane tubulin stabilizers taxol and taxotere and, finally, the antimetabolite gemcitabin, which is active in solid tumours. The process of optimizing their use in a combination with established agents is very complex, with numerous possible drug and schedule regimens. We describe here how a broad panel of drug-resistant small-cell lung cancer (SCLC) cell lines can be used as a model of tumour heterogeneity to aid in the selection of non-cross-resistant regimens. We have selected low-fold (3-10x) drug-resistant sublines from a classic (NCI-H69) and a variant (OC-NYH) SCLC cell line. The resistant cell lines include two sublines with different phenotypes towards alkylating agents (H69/BCNU and NYH/CIS), two sublines with different phenotypes against topo I poisons (NYH/CAM and NYH/TPT) and three multidrug resistant (MDR) sublines (H69/DAU, NYH/VM, and H69/VP) with combinations of mdr1 and MRP overexpression as well as topoisomerase II (topo II) down-regulation or mutation. Sensitivity to 20 established and new agents was measured in a standardized clonogenic assay. Resistance was highly drug specific. Thus, none of the cell lines was resistant to all drugs. In fact, all resistant cell lines exhibited patterns of collateral sensitivity to various different classes of drugs. The most intriguing pattern was collateral sensitivity to gemcitabin in two cell lines and to ara-C in five drug-resistant cell lines, i.e. in all lines except the lines resistant to topo I poisons. Next, all sensitivity patterns in the nine cell lines were compared by correlation analysis. A high correlation coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous.
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影响因子：
168.9
作者：
HANSEN, HH
通讯作者：
HANSEN, HH
影响因子：
5.8
作者：
JENSEN, PB;SORENSEN, BS;HANSEN, HH
通讯作者：
HANSEN, HH
影响因子：
8.8
作者：
JENSEN, PB;CHRISTENSEN, IJ;VINDELOV, L
通讯作者：
VINDELOV, L
影响因子：
3
作者：
JENSEN, PB;ROED, H;HANSEN, HH
通讯作者：
HANSEN, HH
DOI：
10.1016/0277-5379(87)90012-5
发表时间：
1987-02-01
期刊：
EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY
影响因子：
--
作者：
ROED, H;CHRISTENSEN, IJ;HANSEN, HH
通讯作者：
HANSEN, HH