Gurnani M, Lipari P, Dell J, Shi B, Nielsen L L
Tumor Biology Department, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Cancer Chemother Pharmacol. 1999;44(2):143-51. doi: 10.1007/s002800050959.
Adenovirus-mediated p53 gene therapy for cancer is currently undergoing phase I/II clinical trials. The drug used in our clinical trials (p53 Ad; ACN53; SCH58500) consists of a replication-deficient, type 5 adenovirus vector expressing human wildtype p53 tumor suppressor under the control of the cytomegalovirus promoter. In preclinical models, p53 Ad has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53, both in vitro and in vivo. Results from early clinical trials using p53 gene therapy by itself support optimism for the future of this therapeutic approach. However, it is likely that many phase II/III trials will incorporate an arm comparing traditional chemotherapy against chemotherapy combined with p53 gene therapy. Therefore, it is important to study possible interactions between p53 Ad and chemotherapeutic drugs in preclinical models before starting the clinical trials.
Proliferation of tumor cells was quantitated after incubation with various combinations of p53 Ad and chemotherapeutic drugs. Human tumor xenografts in scid mice were dosed with intraperitoneal or intratumoral p53 Ad with or without chemotherapeutic drugs and the tumor burden after therapy monitored.
p53 Ad combined with cisplatin, doxorubicin, 5-fluorouracil, methotrexate, or etoposide inhibited cell proliferation more effectively than chemotherapy alone in SCC-9 head and neck, SCC-15 head and neck, SCC-25 head and neck, SK-OV-3 ovarian, DU-145 prostate, MDA-MB-468 breast, and MDA-MB-231 breast tumor cells. No obvious dependence on dosing schedule was observed. Greater anticancer efficacy was also demonstrated in four human tumor xenograft models in vivo. Of particular significance, there was enhanced efficacy using the three drug combination of p53 Ad, cisplatin, and paclitaxel in an ovarian cancer model.
These results support the combination of p53 gene therapy with chemotherapy in clinical trials.
腺病毒介导的癌症p53基因治疗目前正在进行I/II期临床试验。我们临床试验中使用的药物（p53 Ad；ACN53；SCH58500）由一种复制缺陷型5型腺病毒载体组成，该载体在巨细胞病毒启动子的控制下表达人野生型p53肿瘤抑制因子。在临床前模型中，p53 Ad在体外和体内对多种含有无功能p53的人类肿瘤类型均具有治疗效果。早期单独使用p53基因治疗的临床试验结果为这种治疗方法的未来带来了乐观预期。然而，许多II/III期试验可能会纳入一个比较传统化疗与p53基因治疗联合化疗的组。因此，在开始临床试验之前，在临床前模型中研究p53 Ad与化疗药物之间可能的相互作用非常重要。
用p53 Ad和化疗药物的各种组合孵育后，对肿瘤细胞的增殖进行定量分析。给scid小鼠体内的人肿瘤异种移植瘤腹腔内或瘤内注射p53 Ad，同时给予或不给予化疗药物，并监测治疗后的肿瘤负荷。
在SCC - 9头颈癌、SCC - 15头颈癌、SCC - 25头颈癌、SK - OV - 3卵巢癌、DU - 145前列腺癌、MDA - MB - 468乳腺癌和MDA - MB - 231乳腺癌细胞中，p53 Ad与顺铂、阿霉素、5 - 氟尿嘧啶、甲氨蝶呤或依托泊苷联合使用比单独化疗更有效地抑制细胞增殖。未观察到对给药方案有明显依赖性。在四种人肿瘤异种移植瘤体内模型中也显示出更大的抗癌效果。特别重要的是，在一个卵巢癌模型中，p53 Ad、顺铂和紫杉醇三联药物组合显示出增强的疗效。
这些结果支持在临床试验中将p53基因治疗与化疗联合使用。
