CONFLUENCE-DEPENDENT RESISTANCE IN HUMAN COLON CANCER-CELLS - ROLE OF REDUCED DRUG ACCUMULATION AND LOW INTRINSIC CHEMOSENSITIVITY OF RESTING CELLS
CONFLUENCE-DEPENDENT RESISTANCE IN HUMAN COLON CANCER-CELLS - ROLE OF REDUCED DRUG ACCUMULATION AND LOW INTRINSIC CHEMOSENSITIVITY OF RESTING CELLS
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DOI：
10.1002/ijc.2910500502
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发表时间：
1992-03-12
影响因子：
6.4
通讯作者：
CHAUFFERT, B
中科院分区：
文献类型：
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作者：
DIMANCHEBOITREL, MT;PELLETIER, H;CHAUFFERT, B
HT 29人结肠癌细胞对阿霉素（DXR）、长春新碱（VCR）、足叶乙甙（VP 16）、顺铂（CDDP）、美法仑（L-PAM）和5-氟尿嘧啶（4FU）的体外敏感性随细胞培养密度的增加而显著降低。对于某些药物，汇合依赖性耐药（CDR）部分是由于细胞内药物蓄积减少; DXR、VCR和VP 16的非汇合细胞与汇合细胞的平均细胞内药物含量比值（NC/C）分别为2.5、4.1和7.4。改变药物渗透与汇合可能与减少质膜流动性，如通过荧光偏振法测量。对于L-PAM（NC/C = 1.0）、CDDP（NC/C = 1.2）和5 FU（NC/C = 1.8），药物细胞内蓄积的减少为零或微弱。即使调整培养基中的药物浓度以在融合和非融合细胞中产生相似的细胞内药物含量，仍然证明了DXR和VP 16的融合细胞具有更高的内在耐药性，但VCR（唯一不与DNA直接相互作用的药物）则没有。DXR-和VP 16-诱导的DNA断裂也不太重要，在融合比非融合细胞。流式细胞术、Ki 67单抗识别的核抗原表达和拓扑异构酶II表达显示，融合时CDR与非周期细胞比例增加密切相关。CDR可能是结直肠腺癌化疗敏感性差的一个重要因素。
In vitro sensitivity of HT29 human colon cancer cells to doxorubicin (DXR), vincristine (VCR), etoposide (VP16), cisplatin (CDDP), melphalan (L-PAM) and 5-fluorouracil (4FU) was markedly reduced when cell-culture density increased. For some drugs, confluence-dependent resistance (CDR) was partly due to decreased intracellular drug accumulation; the ratio of mean intracellular drug content of non confluent to confluent cells (NC/C) was 2.5 for DXR, 4.1 for VCR and 7.4 for VP16. Altered drug penetration with confluence could be related to decrease of plasma membrane fluidity as measured by the fluorescence polarization method. Reduction of drug intracellular accumulation was nil or weak for L-PAM (NC/C = 1.0), CDDP (NC/C = 1.2) and 5 FU (NC/C = 1.8). Even if drug concentration was adjusted in culture medium to produce similar intracellular drug content in confluent and non confluent cells, higher intrinsic resistance of confluent cells was still evidenced for DXR and VP16 but not for VCR, the only agent without direct interaction with DNA. DXR- and VP16-induced DNA breakage was also less important in confluent than in non-confluent cells. CDR appeared closely related to an increased proportion of non-cycling cells at confluence, as demonstrated by flow cytometry, expression of nuclear antigen recognized by Ki67 MAb and expression of topoisomerase II. CDR is probably a major factor in the poor sensitivity of colorectal adenocarcinomas to chemotherapy.