Border Biomedical Research Center, University of Texas at El Paso (UTEP), El Paso, TX, USA.
Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Clin Exp Med. 2021 Feb;21(1):149-159. doi: 10.1007/s10238-020-00666-9. Epub 2020 Oct 13.
Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (CTX; 500 mg/m i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.) in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include inhibition of angiogenesis, direct cytotoxic effects on cancer cells, and, at least for drugs such as CTX, activation of the immune system. To further evaluate the latter, we carried out an immune system multiplex 14-cytokine profiling of plasma samples that were available (for day 0, day 28, and day 56) from 31 of the 38 patients in the above-noted clinical trial. Our results show that pre-treatment plasma-level cutoffs of interferon gamma (> 12.84 pg/ml), sCD40L (< 2168 pg/ml), interferon alpha 2 (> 55.11 pg/ml), and IL-17a (< 15.1 pg/ml) were predictive markers for those patients with better progression-free survival (p < .05 for each cytokine). After 28 days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and IL-6 (< 130 pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon gamma and sCD40L after 56 days of therapy. We observed minimal changes in cytokine profiles, from baseline, as a consequence of the metronomic therapy, with the exception of an elevation of IL-6 and IL-8 levels 28 days (and 56 days) after treatment started (p < 0.05). Our results indicate that a selective cytokine elevation involves IL-6 and IL-8, following metronomic chemotherapy administration. In addition, interferon gamma and sCD40L may be potential biomarkers for gastrointestinal cancer patients that are likely to benefit from metronomic chemotherapy. Our study contributes to our understanding of the mechanisms of action of metronomic chemotherapy, and the cytokine profiling we describe may guide future selection of gastrointestinal cancer patients for UFT/CTX/celecoxib combination metronomic chemotherapy.
节拍化疗在多种恶性肿瘤中显示出有前景的抗肿瘤活性。我们之前报道了一项 II 期临床试验，该试验使用节拍 UFT（一种氟尿嘧啶前体药物；每天两次，每次 100mg 口服）和环磷酰胺（CTX；第 1 天静脉推注 500mg，然后每天口服 50mg）联合塞来昔布（每天两次，每次 200mg 口服）治疗 38 例晚期难治性胃肠道肿瘤患者。节拍化疗的作用机制包括抑制血管生成、直接杀伤癌细胞，至少对于 CTX 等药物而言，还能激活免疫系统。为了进一步评估后者，我们对上述临床试验中 38 例患者中有可用（第 0 天、第 28 天和第 56 天）的 31 例患者的血浆样本进行了免疫多因子 14 细胞因子分析。我们的结果表明，干扰素 γ（IFN-γ）（>12.84pg/ml）、sCD40L（<2168pg/ml）、干扰素 α 2（IFN-α2）（>55.11pg/ml）和 IL-17a（<15.1pg/ml）的预处理血浆水平是预测患者无进展生存期更好的标志物（每种细胞因子的 p 值均<.05）。在节拍治疗 28 天后，sCD40L、IL-17a 和 IL-6（<130pg/ml）的血浆水平可作为无进展生存期改善的预测因子，治疗 56 天后 IFN-γ和 sCD40L 也可作为预测因子。除了治疗开始后第 28 天（和第 56 天）IL-6 和 IL-8 水平升高外（p<.05），我们观察到细胞因子谱从基线开始的变化很小。我们的结果表明，在接受节拍化疗后，除了 IL-6 和 IL-8 外，还会选择性地升高细胞因子。此外，IFN-γ和 sCD40L 可能是可能从节拍化疗中受益的胃肠道癌患者的潜在生物标志物。我们的研究有助于我们了解节拍化疗的作用机制，我们描述的细胞因子谱可能指导未来选择胃肠道癌患者接受 UFT/CTX/塞来昔布节拍化疗。
