Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, 93053, Regensburg, Germany.
BMC Cancer. 2022 Jan 31;22(1):125. doi: 10.1186/s12885-021-09125-4.
Drug-drug interaction (DDI), which can occur at the pharmacokinetics and/or the pharmacodynamics (PD) levels, can increase or decrease the therapeutic or adverse response of a drug itself or a combination of drugs. Cancer patients often receive, along their antineoplastic agents, antibiotics such as ß-lactams to treat or prevent infection. Despite the narrow therapeutic indices of antibiotics and antineoplastic agents, data about their potential interaction are insufficient. 5-fluorouracil (5-FU), widely used against colon cancer, is known for its toxicity and large intra- and inter- individual variability. Therefore, knowledge about its interaction with antibiotics is crucial.
In this study, we evaluated at the PD levels, against HCT-116 colon cancer cells, DDI between 5-FU and several ß-lactams (ampicillin, benzypenicillin, piperacillin, meropenem, flucloxacillin, ceftazidime (CFT), and cefepime (CFP)), widely used in intensive care units. All drugs were tested at clinically achieved concentrations. MTT assay was used to measure the metabolic activity of the cells. Cell cycle profile and apoptosis induction were monitored, in HCT-116 and DLD-1 cells, using propidium iodide staining and Caspase-3/7 activity assay. The uptake of CFT and CFP by the cells was measured using LC-MS/MS method.
Our data indicate that despite their limited uptake by the cells, CFT and CFP (two cephalosporins) antagonized significantly 5-FU-induced S-phase arrest (DLD-1 cells) and apoptosis induction (HCT-116 cells). Remarkably, while CFP did not affect the proliferation of colon cancer cells, CFT inhibited, at clinically relevant concentrations, the proliferation of DLD-1 cells via apoptosis induction, as evidenced by an increase in caspase 3/7 activation. Unexpectedly, 5-FU also antagonized CFT's induced cell death in DLD-1 cells.
This study shows that CFP and CFT have adverse effects on 5-FU's action while CFT is a potent anticancer agent that inhibits DLD-1 cells by inducing apoptotic cell death. Further studies are needed to decipher the mechanism(s) responsible for CFT's effects against colon cancer as well as the observed antagonism between CFT, CFP, and 5-FU with the ultimate aim of translating the findings to the clinical settings.
药物-药物相互作用（DDI）可发生在药代动力学和/或药效学（PD）水平，可增加或降低药物本身或联合用药的治疗或不良反应。癌症患者在接受抗肿瘤药物治疗的同时，常需使用β-内酰胺类抗生素（如头孢菌素）来治疗或预防感染。尽管抗生素和抗肿瘤药物的治疗指数较窄，但关于其潜在相互作用的数据仍不足。氟尿嘧啶（5-FU）广泛用于治疗结肠癌，其毒性和个体内、个体间的变异性较大。因此，了解其与抗生素的相互作用至关重要。
在这项研究中，我们在 PD 水平上评估了氟尿嘧啶与几种β-内酰胺类抗生素（氨苄西林、苯唑西林、哌拉西林、美罗培南、氟氯西林、头孢他啶（CFT）和头孢吡肟（CFP））之间的相互作用，这些抗生素广泛应用于重症监护病房。所有药物均在临床达到的浓度下进行测试。MTT 法用于测量细胞的代谢活性。使用碘化丙啶染色和 Caspase-3/7 活性测定法监测 HCT-116 和 DLD-1 细胞的细胞周期谱和凋亡诱导。使用 LC-MS/MS 法测量 CFT 和 CFP 被细胞摄取的情况。
我们的数据表明，尽管细胞摄取有限，CFT 和 CFP（两种头孢菌素）显著拮抗氟尿嘧啶诱导的 S 期阻滞（DLD-1 细胞）和凋亡诱导（HCT-116 细胞）。值得注意的是，虽然 CFP 不影响结肠癌细胞的增殖，但 CFT 以诱导细胞凋亡的方式抑制 DLD-1 细胞的增殖，这一点在 caspase 3/7 激活增加方面得到了证实。出乎意料的是，氟尿嘧啶也拮抗了 CFT 在 DLD-1 细胞中的诱导细胞死亡作用。
这项研究表明，CFP 和 CFT 对氟尿嘧啶的作用有不良影响，而 CFT 是一种有效的抗癌药物，通过诱导细胞凋亡来抑制 DLD-1 细胞的增殖。需要进一步的研究来阐明 CFT 对结肠癌的作用机制以及 CFT、CFP 和氟尿嘧啶之间观察到的拮抗作用，最终目的是将这些发现转化为临床应用。
