Mallery S R, Pei P, Kang J, Zhu G, Ness G M, Schwendeman S P
College of Dentistry, Department of Oral and Maxillofacial Surgery and Pathology and College of Pharmacy, Division of Pharmaceutics, Ohio State University, Columbus, OH 43210, USA.
Carcinogenesis. 2000 Sep;21(9):1647-53. doi: 10.1093/carcin/21.9.1647.
AIDS-related Kaposi's sarcoma (AIDS-KS), the most prevalent HIV-associated malignancy, is a debilitating, potentially fatal disease. Currently, there is a need for development of AIDS-KS therapies that are not only well tolerated, but also capable of providing sustained remission. Preclinical assessment of pharmacological parameters and therapeutic efficacies are dependent upon in vivo parameters. However, there are currently no animal KS models and mucocutaneous KS cell isolates have proved to be non-tumorigenic in animal hosts. This report describes the development of a murine model that enables in vivo transplantation of 'native' low population doubling level AIDS-KS cells from biopsy-confirmed mucocutaneous lesions. The angiogenic phenotype of in situ AIDS-KS lesions is reconstituted via controlled release of a complete angiogenic peptide, recombinant human basic fibroblast growth factor (bFGF), from locally injectable, biodegradable polylactide-co-glycolide implants. Consequential to the sustained local release of bioactive bFGF, a murine vascular network is established, which facilitates the in vivo transplantation of AIDS-KS cells. Desirable aspects of this model include: low cost murine species, transplantation of non-selected patient cells and use of animal hosts that are T cell-deficient. The transplanted human AIDS-KS cells and extensive murine vascular network create lesions that retain a striking resemblance, at both the gross and microscopic levels, to in situ AIDS-KS tumors. Because the bFGF-induced murine vascular network is analogous to the abundant vascularity present in AIDS-KS lesions, this murine model should provide an excellent vehicle for numerous clinically relevant studies, such as assessment of drug clearance at AIDS-KS lesional sites. Finally, applicability of this method is not restricted to AIDS-related malignancies. Establishment and maintenance of an extensive host vascular network should augment success rates for in vivo transplantation of numerous other human cell strains or lines.
艾滋病相关的卡波西肉瘤（AIDS-KS）是最常见的与HIV相关的恶性肿瘤，是一种使人衰弱的、潜在致命的疾病。目前，需要开发不仅耐受性良好，而且能够提供持续缓解的AIDS-KS疗法。药理学参数和治疗效果的临床前评估依赖于体内参数。然而，目前尚无动物KS模型，并且已证明粘膜皮肤KS细胞分离物在动物宿主中不具有致瘤性。本报告描述了一种小鼠模型的开发，该模型能够对活检确诊的粘膜皮肤病变中“天然”低群体倍增水平的AIDS-KS细胞进行体内移植。通过从局部可注射的、可生物降解的聚丙交酯-乙交酯植入物中可控释放完整的血管生成肽重组人碱性成纤维细胞生长因子（bFGF），原位AIDS-KS病变的血管生成表型得以重建。由于生物活性bFGF的持续局部释放，建立了小鼠血管网络，这有利于AIDS-KS细胞的体内移植。该模型的理想之处包括：低成本的小鼠物种、未选择的患者细胞的移植以及使用T细胞缺陷的动物宿主。移植的人类AIDS-KS细胞和广泛的小鼠血管网络产生的病变在大体和微观水平上都与原位AIDS-KS肿瘤极为相似。由于bFGF诱导的小鼠血管网络类似于AIDS-KS病变中存在的丰富血管，该小鼠模型应为众多临床相关研究提供一个极佳的载体，如评估AIDS-KS病变部位的药物清除情况。最后，该方法的适用性不限于艾滋病相关的恶性肿瘤。建立和维持广泛的宿主血管网络应提高许多其他人类细胞株或系体内移植的成功率。
