Kakinoki Yasutaka, Kubota Hiroya, Yamamoto Yasushi
Department of Internal Medicine, Asahikawa Kosei Hospital, Asahikawa, Japan.
Int J Hematol. 2004 Jan;79(1):55-62. doi: 10.1007/BF02983535.
The present study was performed to examine whether the expression of CD64 Fc gamma receptor type I (FcgammaRI) on both neutrophils and monocytes can be modulated by multiple daily administrations of granulocyte colony-stimulating factor (G-CSF) to patients with non-Hodgkin's lymphoma in neutropenia caused by CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. The expression of CD64 was determined by flow cytometric analysis at the following time points: before chemotherapy, at the nadir of the neutrophil count, at the fifth day after the start of G-CSF administration, and at more than 8 days after the start of G-CSF administration. CD64 expression was enhanced in patients given G-CSF during CHOP treatment, whereas CD64 expression remained unchanged in patients not given G-CSF CD64 expression levels on both neutrophils and monocytes were significantly up-regulated by the daily administration of G-CSF and reached peak levels at day 5 (P = .0007). Thereafter, expression on both cell types remained at almost the same levels as on day 5 for the rest of the treatment course, even though G-CSF therapy continued for 3 to 5 more days. Interestingly, CD64 expression on monocytes was already increased significantly (P = .0001) at the nadir of the neutrophil count relative to the baseline before chemotherapy and then was additionally up-regulated by day 5 after the start of G-CSF injections (P = .019). In antibody-dependent cellular cytotoxicity assays, we found that rituximab-mediated cell lysis was significantly enhanced at day 5 after the start of G-CSF treatment (P = .01). In conclusion, this study shows that multiple doses of G-CSF administered to lymphoma patients with neutropenia due to CHOP chemotherapy can enhance CD64 expression on both neutrophils and monocytes. Peak CD64 levels are reached at day 5 of G-CSF treatment, resulting in an activation of the rituximab-mediated antitumor ability of these effector cells. This finding may be useful in determining the optimal timing of administration for an antibody such as rituximab in a chemotherapeutic strategy designed to exert a maximal effect against tumor cells.
本研究旨在探讨对于因CHOP（环磷酰胺、阿霉素、长春新碱和泼尼松）化疗导致中性粒细胞减少的非霍奇金淋巴瘤患者，每日多次给予粒细胞集落刺激因子（G-CSF）是否能调节中性粒细胞和单核细胞上CD64 Fcγ受体I型（FcγRI）的表达。通过流式细胞术分析在以下时间点测定CD64的表达：化疗前、中性粒细胞计数最低点、开始给予G-CSF后第5天以及开始给予G-CSF后8天以上。在CHOP治疗期间给予G-CSF的患者中，CD64表达增强，而未给予G-CSF的患者中CD64表达保持不变。每日给予G-CSF可使中性粒细胞和单核细胞上的CD64表达水平显著上调，并在第5天达到峰值水平（P = .0007）。此后，即使G-CSF治疗再持续3至5天，在治疗过程的剩余时间里，两种细胞类型上的表达仍保持与第5天几乎相同的水平。有趣的是，相对于化疗前的基线水平，在中性粒细胞计数最低点时，单核细胞上的CD64表达已显著增加（P = .0001），然后在开始注射G-CSF后第5天进一步上调（P = .019）。在抗体依赖性细胞毒性试验中，我们发现G-CSF治疗开始后第5天，利妥昔单抗介导的细胞裂解显著增强（P = .01）。总之，本研究表明，对于因CHOP化疗导致中性粒细胞减少的淋巴瘤患者，多次给予G-CSF可增强中性粒细胞和单核细胞上的CD64表达。在G-CSF治疗第5天达到CD64峰值水平，导致这些效应细胞的利妥昔单抗介导的抗肿瘤能力激活。这一发现可能有助于确定在旨在对肿瘤细胞发挥最大作用的化疗策略中，如利妥昔单抗等抗体的最佳给药时机。
