Tanino H, Oura S, Hoffman R M, Kubota T, Furukawa T, Arimoto J, Yoshimasu T, Hirai I, Bessho T, Suzuma T, Sakurai T, Naito Y
Department of Thoracic and Cardiovascular Surgery, Wakayama Medical College, Japan.
Anticancer Res. 2001 Nov-Dec;21(6A):4083-6.
Recurrent breast cancer has a very poor response rate to chemotherapy. To understand the degree of acquisition of multidrug resistance in recurrent disease, 24 recurrent breast tumors and 127 primary tumors were evaluated and compared for chemosensitivity in the histoculture drug response assay (HDRA). The evaluation rate was 98.8%. The HDRA utilizes 3-dimensional culture of human tumors on collagen-gel rafts. Doxorubicin (DXR), 5-fluorouracil (5-FU) and mitomycin C (MMC) were tested as standard agents and cisplatin (CDDP) as a candidate agent on surgical specimen of breast cancer in the HDRA. In vitro drug exposure in the HDRA was for 7 days. At the end of the assay, tumor response was assessed by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The mean inhibition rates of primary tumors vs. recurrent tumors were 57.9% and 38.6% for DXR (p<0.0005); 59.9% and 42.8% for MMC (p<0.01); 49.0% and 33.4% for 5-FU (p<0.01); and 34.5% and 16.0% for CDDP (p<0.005), respectively. The recurrent cases were pretreated clinically with CAF (cyclophosphamide, DXR and 5-FU), CEF (cyclophosphamide, epirubicin and 5-FU) or CMF (cyclophosphamide, methotrexate and 5-FU). In the CAF and CEF group, the HDRA sensitivity to CDDP was significantly lower in recurrent disease (p<0.005) than that of primary breast cancer suggesting that one agent can induce resistance to another. This is further suggested by the fact that 64.7% of the recurrent cases were resistant to all 4 agents tested as opposed to 27% of the primary cases and that only 5.9% of the recurrent cases were sensitive to three or more agents as opposed to 18% of the primary cases. The correlation of the HDRA results to clinical outcome in the study was 80.0% with 15 cases evaluated consisting of 5 true positives, 3 false positives, 7 true negatives and no false negatives. Thus, the HDRA gives useful clinical information, in particular for the specific individualized treatment design necessary to overcome the multidrug resistance problem of recurrent breast cancer.
复发性乳腺癌对化疗的反应率非常低。为了解复发性疾病中多药耐药性的获得程度，在组织培养药物反应试验（HDRA）中对24例复发性乳腺肿瘤和127例原发性肿瘤进行了化疗敏感性评估和比较。评估率为98.8%。HDRA利用人肿瘤在胶原凝胶筏上进行三维培养。在HDRA中，将阿霉素（DXR）、5-氟尿嘧啶（5-FU）和丝裂霉素C（MMC）作为标准药物进行测试，顺铂（CDDP）作为候选药物在乳腺癌手术标本上进行测试。HDRA中的体外药物暴露时间为7天。在试验结束时，通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）的减少来评估肿瘤反应。DXR对原发性肿瘤和复发性肿瘤的平均抑制率分别为57.9%和38.6%（p<0.0005）；MMC分别为59.9%和42.8%（p<0.01）；5-FU分别为49.0%和33.4%（p<0.01）；CDDP分别为34.5%和16.0%（p<0.005）。复发病例临床上曾接受CAF（环磷酰胺、DXR和5-FU）、CEF（环磷酰胺、表柔比星和5-FU）或CMF（环磷酰胺、甲氨蝶呤和5-FU）治疗。在CAF和CEF组中，复发性疾病对CDDP的HDRA敏感性显著低于原发性乳腺癌（p<0.005），这表明一种药物可诱导对另一种药物的耐药性。这一点进一步体现在以下事实上：64.7%的复发病例对所有4种测试药物耐药，而原发性病例为27%；只有5.9%的复发病例对三种或更多药物敏感，而原发性病例为18%。在该研究中，HDRA结果与临床结局的相关性为80.0%，评估的15例病例包括5例假阳性、3例假阴性、7例真阴性且无假阴性。因此，HDRA可提供有用的临床信息，特别是对于克服复发性乳腺癌多药耐药问题所需的特定个体化治疗设计。
