Rakhmilevich Alexander L, Hooper Andrea T, Hicklin Daniel J, Sondel Paul M
K4/413 Clinical Science Center, Department of Human Oncology, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792, USA.
Mol Cancer Ther. 2004 Aug;3(8):969-76.
We have shown previously that interleukin-12 (IL-12) gene therapy induced strong antitumor effects in several syngeneic murine tumor models including 4T1 mammary adenocarcinoma. Antiangiogenic treatment with a monoclonal antibody (mAb) directed against the vascular endothelial growth factor receptor-2 (VEGFR-2) is another promising treatment approach that can cause transient suppression of tumor growth. We hypothesized that the combination of IL-12 gene therapy and anti-VEGFR-2 mAb will achieve better antitumor and antimetastatic effects against 4T1 adenocarcinoma than each treatment alone via implementation of different mechanisms. Administration of anti-VEGFR-2 mAb into BALB/c mice bearing s.c. 4T1 tumors induced significant suppression of tumor growth, as did intratumoral administration of naked IL-12 DNA. The combined treatment with anti-VEGFR-2 mAb and IL-12 DNA resulted in significantly enhanced inhibition of tumor growth as compared with each treatment alone. This combination was also effective against spontaneous lung metastases. In T-cell-deficient nude mice, both IL-12 DNA and anti-VEGFR-2 mAb were effective in suppressing tumor growth. In T-cell- and natural killer cell-deficient scid/beige mice, only anti-VEGFR-2 mAb was effective, suggesting that natural killer cells are involved in the antitumor effects induced by IL-12 DNA. In both types of immunodeficient mice, the combination of anti-VEGFR-2 mAb and IL-12 DNA was as effective in suppressing 4T1 tumor growth as anti-VEGFR-2 mAb alone. Antitumor effects of anti-VEGFR-2 mAb were associated with the inhibition of angiogenesis within the tumors, whereas the antiangiogenic effect of IL-12 gene therapy was not detected. Our results show a therapeutic benefit of combining IL-12 gene therapy and anti-VEGFR-2 mAb for cancer treatment.
我们之前已经表明，白细胞介素-12（IL-12）基因疗法在包括4T1乳腺腺癌在内的几种同基因小鼠肿瘤模型中诱导了强烈的抗肿瘤作用。用针对血管内皮生长因子受体-2（VEGFR-2）的单克隆抗体（mAb）进行抗血管生成治疗是另一种有前景的治疗方法，可导致肿瘤生长的短暂抑制。我们假设，IL-12基因疗法和抗VEGFR-2 mAb的联合应用将通过不同机制的实施，比单独使用每种治疗方法对4T1腺癌产生更好的抗肿瘤和抗转移效果。将抗VEGFR-2 mAb给予皮下接种4T1肿瘤的BALB/c小鼠，可显著抑制肿瘤生长，瘤内注射裸IL-12 DNA也有同样效果。与单独使用每种治疗方法相比，抗VEGFR-2 mAb和IL-12 DNA联合治疗导致肿瘤生长的抑制作用显著增强。这种联合对自发性肺转移也有效。在T细胞缺陷的裸鼠中，IL-12 DNA和抗VEGFR-2 mAb均能有效抑制肿瘤生长。在T细胞和自然杀伤细胞缺陷的scid/beige小鼠中，只有抗VEGFR-2 mAb有效，这表明自然杀伤细胞参与了IL-12 DNA诱导的抗肿瘤作用。在这两种免疫缺陷小鼠中，抗VEGFR-2 mAb和IL-12 DNA联合应用在抑制4T1肿瘤生长方面与单独使用抗VEGFR-2 mAb效果相同。抗VEGFR-2 mAb的抗肿瘤作用与肿瘤内血管生成的抑制有关，而未检测到IL-12基因疗法的抗血管生成作用。我们的结果显示了IL-12基因疗法和抗VEGFR-2 mAb联合用于癌症治疗的治疗益处。
