Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
Pharmaceutical Candidate Optimization, Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Princeton, NJ 08540, USA.
Cells. 2020 Nov 21;9(11):2520. doi: 10.3390/cells9112520.
Non-Hodgkin's lymphoma (NHL) is a malignant cancer originating in the lymphatic system with a 25-30% mortality rate. CHOP, consisting of cyclophosphamide (CPA), doxorubicin, vincristine, and prednisone, is a first-generation chemotherapy extensively used to treat NHL. However, poor survival rates among patients in advanced stages of NHL shows a need to improve this standard of care treatment. CPA, an integral component of CHOP, is a prodrug that requires CYP2B6-mediated bioactivation to 4-hydroxy-CPA (4-OH-CPA). The expression of CYP2B6 is transcriptionally regulated by the constitutive androstane receptor (CAR, NRi13). We have previously demonstrated that the induction of hepatic CYP2B6 by CITCO, a selective human CAR (hCAR) agonist, results in CHOP's enhanced antineoplastic effects in vitro. Here, we investigate the in vivo potential of CITCO as an adjuvant of CPA-based NHL treatment in a hCAR-transgenic mouse line. Our results demonstrate that the addition of CITCO to the CHOP regimen leads to significant suppression of the growth of EL-4 xenografts in hCAR-transgenic mice accompanied by reduced expression of cyclin-D1, ki67, Pcna, and increased caspase 3 fragmentation in tumor tissues. CITCO robustly induced the expression of cyp2b10 (murine ortholog of CYP2B6) through hCAR activation and increased plasma concentrations of 4-OH-CPA. Comparing to intraperitoneal injection, oral gavage of CITCO results in optimal hepatic cyp2b10 induction. Our in vivo studies have collectively uncovered CITCO as an effective facilitator for CPA-based NHL treatment with a pharmacokinetic profile favoring oral administration, promoting CITCO as a promising adjuvant candidate for CPA-based regimens.
非霍奇金淋巴瘤（NHL）是一种起源于淋巴系统的恶性肿瘤，死亡率为 25-30%。CHOP 由环磷酰胺（CPA）、多柔比星、长春新碱和泼尼松组成，是一种广泛用于治疗 NHL 的第一代化疗药物。然而，晚期 NHL 患者的生存率仍然较低，这表明需要改进这种标准治疗方法。CPA 是 CHOP 的一个组成部分，是一种前药，需要 CYP2B6 介导的生物转化为 4-羟基-CPA（4-OH-CPA）。CYP2B6 的表达受组成型雄烷受体（CAR，NRi13）转录调控。我们之前已经证明，选择性人 CAR（hCAR）激动剂 CITCO 诱导肝 CYP2B6 的表达可增强 CHOP 在体外的抗肿瘤作用。在这里，我们研究了 CITCO 作为基于 CPA 的 NHL 治疗辅助剂在 hCAR 转基因小鼠中的体内潜力。我们的结果表明，在 hCAR 转基因小鼠中，CITCO 与 CHOP 联合治疗可显著抑制 EL-4 异种移植瘤的生长，同时降低肿瘤组织中环磷酰胺、ki67、Pcna 的表达，增加 caspase 3 片段的形成。CITCO 通过 hCAR 激活可强烈诱导 cyp2b10（CYP2B6 的鼠同源物）的表达，并增加血浆中 4-OH-CPA 的浓度。与腹腔注射相比，CITCO 口服给药可使肝 cyp2b10 诱导达到最佳效果。我们的体内研究共同揭示了 CITCO 作为基于 CPA 的 NHL 治疗的有效促进剂，具有有利于口服给药的药代动力学特征，使 CITCO 成为基于 CPA 的方案的有前途的辅助候选药物。
