Kreuser E D, Wadler S, Thiel E
Department of Hematology and Oncology, Klinikum Steglitz, Free University of Berlin, Germany.
Recent Results Cancer Res. 1995;139:371-82. doi: 10.1007/978-3-642-78771-3_28.
The combination of cytokines and cytotoxic drugs offers a new approach to increase the therapeutic index in the treatment of neoplastic diseases. There is no consensus on optimal strategies for combining these agents so far. The molecular mechanisms underlying the interaction, however, should be defined in order to design clinical trials based on preclinical rationales. The broad spectrum of cytotoxic drugs whose activity can be enhanced by cytokines argues for multiple levels of drug interaction in vitro: alteration in the cellular drug uptake, modulation of drug target enzymes, and changes in metabolism or disposition of a drug. In vivo interaction between cytokines and cytotoxic agents involves an additional layer of complexity because of the effects of cytokines on the host immune system and on drug-metabolizing enzymes. A major mechanism involved in the synergistic interaction of interferon (IFN) and 5-fluorouracil (5-FU) seems to be the increase of active 5-FU metabolites by IFN. Moreover, IFN can reverse resistance against 5-FU by inhibiting the overexpression of thymidylate synthase. The absence of cytokinetic effects of IFN and FU argues against the recruitment of Gs cells into the cell cycle. Topoisomerase has emerged as a critical intracellular target of cytotoxic drugs. There is convincing evidence that the synergy between tumor necrosis factor (TNF) and topoisomerase-targeted intercalative (Adriamycin, doxorubicin hydrochloride; m-AMSA, amsacrine; mitoxantrone) and nonintercalative (VM-16, etoposide; VM-26, teniposide) drugs is related to a rapid increase in specific activity of topoisomerase I and II, resulting in enhanced DNA strand breaks and cleavage complex. Furthermore, sensitivity to topoisomerase II targeted drugs can be enhanced by granulocyte colony-stimulating factor (G-CSF) through elevated enzyme activity in tumor cell response to G-CSF. The synergistic interaction between cytokines and cytotoxic agents seems to be sequence dependent. It has recently been demonstrated that newly synthesized metal compounds and IFN are synergistic only after preincubation with cytokines. Cytokines can modulate expression of adhesion receptors on tumor cell lines, thereby influencing their metastatic potential. A considerable number of phase II trials with combination of cytokines and cytotoxic drugs based on these mechanisms have demonstrated promising response rates and tolerable toxicity. Phase III trials are currently in progress to identify enhanced activity combining cytokines and cytotoxic drugs in the treatment of malignancies.
细胞因子与细胞毒性药物联合使用为提高肿瘤疾病治疗的治疗指数提供了一种新方法。目前对于联合使用这些药物的最佳策略尚无共识。然而，为了基于临床前理论设计临床试验，应明确两者相互作用的分子机制。细胞因子可增强多种细胞毒性药物的活性，这表明在体外存在多个药物相互作用水平：细胞对药物摄取的改变、药物靶酶的调节以及药物代谢或处置的变化。由于细胞因子对宿主免疫系统和药物代谢酶的影响，细胞因子与细胞毒性药物在体内的相互作用涉及另一层复杂性。干扰素（IFN）与5-氟尿嘧啶（5-FU）协同相互作用的主要机制似乎是IFN增加了活性5-FU代谢产物。此外，IFN可通过抑制胸苷酸合成酶的过表达来逆转对5-FU的耐药性。IFN和FU不存在细胞动力学效应，这表明Gs细胞未被募集进入细胞周期。拓扑异构酶已成为细胞毒性药物的关键细胞内靶点。有令人信服的证据表明，肿瘤坏死因子（TNF）与靶向拓扑异构酶的嵌入性（阿霉素、盐酸多柔比星；m-AMSA、安吖啶；米托蒽醌）和非嵌入性（VM-16、依托泊苷；VM-26、替尼泊苷）药物之间的协同作用与拓扑异构酶I和II的比活性迅速增加有关，从而导致DNA链断裂和裂解复合物增加。此外，粒细胞集落刺激因子（G-CSF）可通过提高肿瘤细胞对G-CSF反应中的酶活性来增强对靶向拓扑异构酶II药物的敏感性。细胞因子与细胞毒性药物之间的协同相互作用似乎取决于给药顺序。最近已证明，新合成的金属化合物与IFN仅在与细胞因子预孵育后才具有协同作用。细胞因子可调节肿瘤细胞系上黏附受体的表达，从而影响其转移潜能。基于这些机制进行的大量细胞因子与细胞毒性药物联合的II期试验已显示出有前景的缓解率和可耐受的毒性。目前正在进行III期试验，以确定细胞因子与细胞毒性药物联合治疗恶性肿瘤时增强的活性。
