DiPaola R S, Aisner J
Department of Medicine, Robert Wood Johnson Medical School, UMDNJ, The Cancer Institute of New Jersey, New Brunswick, USA.
Semin Oncol. 1999 Feb;26(1 Suppl 2):112-6.
Most prostate cancers eventually develop resistance to hormonal therapy and chemotherapies. Many mechanisms for resistance to chemotherapy have been identified. Mutations or inactivation of the p53 suppressor gene and overexpression of bcl-2 are among such mechanisms. Mutations in the p53 gene can lead to resistance to certain chemotherapy agents, and such mutations are seen more often in metastatic than in primary prostate cancers. Thus, agents that are active in the setting of mutated p53 may have some advantage in prostate cancer. Overexpression of bcl-2 occurs frequently in prostate cancer and is associated with both hormonal therapy and chemotherapy resistance. In experimental systems, bcl-2 overexpression occurs after androgen deprivation and transfection of bcl-2 into sensitive cell lines makes them resistant to chemotherapy and hormonal therapies. Bcl-2 can be inactivated by phosphorylation as occurs with taxanes. The retinoids, as a class, can inhibit the growth of resistant cell lines that overexpress bcl-2, and the combination of interferon (IFN) and cis-retinoic acid (CRA) demonstrated increased antitumor activity. In our cell line model the combination of IFN and CRA greatly enhanced the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on these observations, we conducted a phase I/II trial of CRA and IFN-alpha in patients with biochemical recurrence of prostate cancer. Twenty-six percent achieved a decrease of prostate-specific antigen (PSA), which was correlated to elevated serum transforming growth factor-beta. We then conducted a phase I trial of 13-CRA, IFN-alpha, and escalating doses of paclitaxel. Eighteen patients were treated with 1 mg/kg CRA and 1x10(6) unit IFN on days 1 to 4 and paclitaxel at doses from 100 to 175 mg/m2. Eleven patients received the 175 mg/m2 paclitaxel dose. Two patients in the phase I study achieved partial responses (one cervix and one prostate cancer). We subsequently initiated a phase II study of 13-CRA, IFN-alpha, and paclitaxel in hormone refractory prostate cancer. For entry patients must show progressive disease after androgen ablation. To test the mechanism of action, we are assaying peripheral blood monocytes and, when possible, tumor tissue for bcl-2 expression. As our understanding of the mechanisms of tumor resistance to chemotherapy improves, we will be able to design better approaches in treatment targeted to overcome the mechanisms of resistance.
大多数前列腺癌最终会对激素疗法和化疗产生耐药性。已经确定了许多化疗耐药机制。p53抑癌基因的突变或失活以及bcl-2的过表达都属于此类机制。p53基因的突变可导致对某些化疗药物产生耐药性，并且这种突变在转移性前列腺癌中比在原发性前列腺癌中更常见。因此，对p53突变有效的药物在前列腺癌治疗中可能具有一定优势。bcl-2的过表达在前列腺癌中频繁发生，并且与激素疗法和化疗耐药性都有关。在实验系统中，雄激素剥夺后会出现bcl-2过表达，将bcl-2转染到敏感细胞系中会使其对化疗和激素疗法产生耐药性。bcl-2可通过像紫杉烷那样的磷酸化作用而失活。作为一类药物，维甲酸可以抑制过表达bcl-2的耐药细胞系的生长，并且干扰素（IFN）和顺式维甲酸（CRA）联合使用显示出增强的抗肿瘤活性。在我们的细胞系模型中，IFN和CRA联合使用极大地增强了紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）的细胞毒性。基于这些观察结果，我们对前列腺癌生化复发患者进行了CRA和干扰素-α的I/II期试验。26%的患者前列腺特异性抗原（PSA）下降，这与血清转化生长因子-β升高相关。然后我们进行了13-CRA、干扰素-α和递增剂量紫杉醇的I期试验。18名患者在第1至4天接受1mg/kg CRA和1×10⁶单位干扰素治疗，并接受100至175mg/m²剂量的紫杉醇治疗。11名患者接受了175mg/m²的紫杉醇剂量。I期研究中有2名患者取得部分缓解（一名宫颈癌患者和一名前列腺癌患者）。随后我们启动了13-CRA、干扰素-α和紫杉醇治疗激素难治性前列腺癌的II期研究。入选患者必须在雄激素去除后出现疾病进展。为了测试作用机制，我们正在检测外周血单核细胞，并尽可能检测肿瘤组织中的bcl-2表达。随着我们对肿瘤化疗耐药机制的理解不断提高，我们将能够设计出更好的针对性治疗方法来克服耐药机制。
