Adenovirus mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer
Adenovirus mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer
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DOI：
10.1007/s002800050959
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发表时间：
1999-08-01
影响因子：
3
通讯作者：
Nielsen, LL
中科院分区：
文献类型：
--
作者：
Gurnani, M;Lipari, P;Nielsen, LL
目的：腺病毒介导的p53基因治疗癌症目前正在进行I/II期临床试验。我们临床试验中使用的药物（p53 Ad; ACN53; SCH58500）是一种复制缺陷的5型腺病毒载体，在巨细胞病毒启动子的控制下表达人类野生型p53肿瘤抑制因子。在临床前模型中，p53 Ad在体内和体外均对多种含有无功能p53的人类肿瘤类型具有治疗效果。使用p53基因疗法的早期临床试验结果本身支持了对这种治疗方法未来的乐观态度。然而，许多II/III期试验可能会纳入一个比较传统化疗与化疗联合p53基因治疗的小组。因此，在临床试验开始之前，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是很重要的。方法：用不同的p53 - Ad联合化疗药物孵育后，定量观察肿瘤细胞的增殖情况。分别给人肿瘤移植小鼠腹腔或瘤内注射p53 Ad和化疗药物，并监测治疗后的肿瘤负荷。结果：p53 Ad联合顺铂、阿霉素、5-氟尿嘧啶、甲氨蝶呤或依托泊苷抑制SCC-9头颈部、SCC-15头颈部、SCC-25头颈部、SK-OV-3卵巢、DU-145前列腺、MDA-MB-468乳腺和MDA-MB-231乳腺肿瘤细胞的细胞增殖比单独化疗更有效。对给药方案无明显依赖性。在体内四种人类肿瘤异种移植模型中也显示出更大的抗癌功效。特别重要的是，在卵巢癌模型中，p53 Ad、顺铂和紫杉醇三种药物联合使用的疗效增强。结论：这些结果支持p53基因治疗联合化疗在临床试验中的应用。
Purpose: 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. Methods: 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. Results: 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. Conclusion: These results support the combination of p53 gene therapy with chemotherapy in clinical trials.