Swenson Stephen D, Silva-Hirschberg Catalina, Markland Francis S
Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Methods Mol Biol. 2020;2068:185-204. doi: 10.1007/978-1-4939-9845-6_10.
Integrin targeting has been shown to be an effective approach for anticancer therapy. We engineered a recombinant disintegrin, vicrostatin (VCN), that binds with high affinity and specificity to the Arg-Gly-Asp (RGD) class of integrins, including αvβ3, αvβ5, and α5β1, involved in tumor invasion and metastasis. We used three different delivery modalities to examine anticancer activity of VCN in mouse models of human ovarian cancer, glioma, and prostate cancer. A female mouse model was used to examine the treatment of established ovarian cancer (OC) using VCN delivered intraperitoneally (IP) weekly either in saline or impregnated in a viscoelastic gel. SKOV3 cells (a human OC cell line) were directly injected IP into immunodeficient mice. We also examined the antitumor activity of radioiodinated VCN delivered intravenously in a human glioma model in nude mice. We evaluated the effectiveness of I-VCN in combination with the DNA alkylating agent temozolomide in limiting glioma growth. Finally, treatment of a bone metastatic model of human prostate cancer (PC) in immunodeficient mice was examined using a liposomal formulation of VCN (LVCN) delivered intravenously. Human PC cells were suspended in a solution of Matrigel and injected into the left tibia of immunodeficient mice. Diameters of both the left and right (control) tibias were measured by caliper repeatedly after VCN treatment was initiated.
整合素靶向已被证明是一种有效的抗癌治疗方法。我们设计了一种重组去整合素，即维克他汀（VCN），它能与参与肿瘤侵袭和转移的包括αvβ3、αvβ5和α5β1在内的RGD类整合素以高亲和力和特异性结合。我们使用三种不同的给药方式来检测VCN在人卵巢癌、神经胶质瘤和前列腺癌小鼠模型中的抗癌活性。使用雌性小鼠模型来检测使用每周腹腔内（IP）注射于盐水中或包埋于粘弹性凝胶中的VCN对已建立的卵巢癌（OC）的治疗效果。将SKOV3细胞（一种人OC细胞系）直接腹腔内注射到免疫缺陷小鼠体内。我们还检测了静脉注射放射性碘化VCN在裸鼠人神经胶质瘤模型中的抗肿瘤活性。我们评估了I-VCN与DNA烷化剂替莫唑胺联合使用在限制神经胶质瘤生长方面的有效性。最后，使用静脉注射的VCN脂质体制剂（LVCN）检测免疫缺陷小鼠中人前列腺癌（PC）骨转移模型的治疗效果。将人PC细胞悬浮于基质胶溶液中并注射到免疫缺陷小鼠的左胫骨中。在开始VCN治疗后，用卡尺反复测量左、右（对照）胫骨的直径。
