Turowski R C, Triozzi P L
Colleges of Pharmacy and Medicine, Arthur G. James Cancer Hospital and Research Institute, Ohio State University Comprehensive Cancer Center, Columbus.
Cancer Invest. 1994;12(6):620-43. doi: 10.3109/07357909409023048.
A number of potential advantages, development of promising new agents, and the discovery of synergy with cytokines or cell products continue to spur research into the application of chemical immunomodulators for the treatment of cancer and AIDS. In preclinical in vitro and in vivo systems, chemical immunomodulators definitely modulate the immune system and have therapeutic efficacy. Although clinical trials have shown the ability of these agents to modulate the human immune system, thus far chemical immunomodulators have generally not fulfilled the therapeutic promise generated in animal models for the treatment of human diseases. While the discrepancy in results between animal models and human trials is obvious, the basis is not apparent. Species differences in elimination kinetics, presentation of active drug at the site of action, and the development of tachyphylaxis have been postulated as reasons for the minimal activity of these agents in humans. In addition, the use of investigational techniques established for cytotoxic agents may not be appropriate for immunomodulators. As with any immunomodulator, determining an optimal immunostimulatory dose and schedule and applying the therapy to patients with minimal tumor burden would perhaps be more appropriate than use of a maximally tolerated dose in patients with advanced disease. A dose-immunological effect relationship has recently been demonstrated for levamisole at doses higher than those used for many years in levamisole trials (99). While research and clinical investigation have identified several potentially useful chemical immunomodulators, the elementary understanding of the biochemical mechanisms involved in immunoregulation remains basic. Future research must elucidate these mechanisms, particularly in humans, to maximize the benefits of chemical immunomodulators as single agents or combined with cytotoxic chemotherapeutic agents, surgery, radiation therapy, other immunomodulators, and antiviral agents.
许多潜在优势、有前景的新药物的开发以及与细胞因子或细胞产物协同作用的发现，持续推动着化学免疫调节剂在癌症和艾滋病治疗应用方面的研究。在临床前的体外和体内系统中，化学免疫调节剂确实能调节免疫系统并具有治疗效果。尽管临床试验已表明这些药物有调节人体免疫系统的能力，但迄今为止，化学免疫调节剂总体上尚未实现动物模型中所产生的治疗人类疾病的前景。虽然动物模型和人体试验结果之间的差异很明显，但其原因尚不明确。消除动力学的种属差异、活性药物在作用部位的呈现以及快速耐受性的发展，已被假定为这些药物在人体中活性极小的原因。此外，为细胞毒性药物建立的研究技术可能不适用于免疫调节剂。与任何免疫调节剂一样，确定最佳免疫刺激剂量和给药方案，并将该疗法应用于肿瘤负荷最小的患者，可能比在晚期疾病患者中使用最大耐受剂量更为合适。最近已证明，左旋咪唑在高于其多年来试验中使用剂量（99）时存在剂量 - 免疫效应关系。虽然研究和临床调查已确定了几种潜在有用的化学免疫调节剂，但对免疫调节所涉及的生化机制的基本理解仍然很基础。未来的研究必须阐明这些机制，特别是在人体中，以最大限度地发挥化学免疫调节剂作为单一药物或与细胞毒性化疗药物、手术、放射治疗、其他免疫调节剂和抗病毒药物联合使用的益处。
