DeLong Peter, Tanaka Tomoyuki, Kruklitis Robb, Henry Adam C, Kapoor Veena, Kaiser Larry R, Sterman Dan H, Albelda Steven M
Thoracic Oncology Laboratory, 8th Floor BRB II/III, University of Pennsylvania Medical Center, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Cancer Res. 2003 Nov 15;63(22):7845-52.
Antitumor effects of cyclooxygenase-2 (COX-2) inhibition have been reported in a wide variety of tumor models and in human cancers, both as chemoprevention and therapy. Human mesothelioma tumors have been shown to overexpress COX-2 and high levels of COX-2 protein have been demonstrated to be a prognostic factor, indicating poor outcome in this tumor. In this study, we determined that inhibition of COX-2 by oral administration of Rofecoxib significantly slowed but did not cure the growth of small tumors in mesothelioma-bearing mice. Large tumors were unaffected. This effect was dependent on the presence of CD8+ T cells and was associated with increased tumor-infiltrating lymphocytes. Because these activities are consistent with a mechanism that results in a decrease in the immunosuppressive environment of the tumor, we additionally examined the effect of COX-2 blockade combined with Ad.IFN-beta therapy, a treatment that we have previously demonstrated results in expansion of antitumor CD8+ CTLs and cures a high percentage of small mesothelioma tumors in mice. Ad.IFN-beta therapy combined with COX-2 inhibition was associated with an increased number of T cells within tumors and resulted in cures of small tumors, significant inhibition of the growth of large established tumors, and inhibition of the growth of metastatic tumor foci after surgical debulking. The additive effects of these modes of treatment suggests that it would be rational to combine COX-2 inhibition with immuno- and immunogene therapy approaches (perhaps in conjunction with surgical debulking) in human clinical trials of treatment of mesothelioma and other tumors.
环氧合酶-2（COX-2）抑制的抗肿瘤作用已在多种肿瘤模型和人类癌症中得到报道，包括化学预防和治疗。人恶性间皮瘤肿瘤已被证明过表达COX-2，并且高水平的COX-2蛋白已被证明是一个预后因素，表明该肿瘤预后不良。在本研究中，我们确定口服罗非昔布抑制COX-2可显著减缓但不能治愈携带间皮瘤小鼠的小肿瘤生长。大肿瘤不受影响。这种作用依赖于CD8+T细胞的存在，并与肿瘤浸润淋巴细胞增加有关。由于这些活性与导致肿瘤免疫抑制环境降低的机制一致，我们还研究了COX-2阻断联合Ad.IFN-β治疗的效果，我们之前已证明这种治疗可导致抗肿瘤CD8+CTL扩增并治愈小鼠中高比例的小间皮瘤肿瘤。Ad.IFN-β治疗联合COX-2抑制与肿瘤内T细胞数量增加有关，并导致小肿瘤治愈、显著抑制大的已形成肿瘤的生长以及在手术减瘤后抑制转移瘤灶的生长。这些治疗方式的相加作用表明，在人恶性间皮瘤和其他肿瘤的治疗临床试验中，将COX-2抑制与免疫和免疫基因治疗方法（可能与手术减瘤联合）相结合是合理的。
