Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
Biomaterials. 2018 Nov;182:35-43. doi: 10.1016/j.biomaterials.2018.08.007. Epub 2018 Aug 7.
Metronomic chemotherapy, which is defined as a low-dose and frequent administration of cytotoxic drugs without drug-free breaks, has been recently emerged as an alternative to traditional MTD therapy and has shown therapeutic benefit in breast cancer patients in numbers of clinical studies. Unlike MTD, metronomic chemotherapy acts by multiple mechanisms including antiangiogenic effect and immunomodulation, but the direct cytotoxic effect only playing a minor role due to the lowered dose. In this light, within the limits of p53-deficient breast cancer, we demonstrate the enhanced anticancer effect of metronomic chemotherapy using doxorubicin when combined with Chk1 inhibitor MK-8776 by specifically augmenting the direct cytotoxic effect on cancer cells. Since the oral drug is greatly favored in metronomic chemotherapy due to the frequent and potential long-term administration, we prepared an oral doxorubicin by producing an ionic complex with deoxycholic acid, which showed sufficient bioavailability and anticancer effect when administered orally. MK-8776 selectively enhanced the cytotoxic effect of low-concentration doxorubicin in p53-deficient breast cancer cells by abrogating the Chk1-dependent cell cycle arrest in vitro. Consistently, combining MK-8776 significantly improved the anticancer effect of the daily administered oral doxorubicin in p53-deficient breast cancer xenografts especially in a lower dose of doxorubicin without evident systemic toxicities. Combination therapy of MK-8776 and metronomic oral doxorubicin would be thus promising in the treatment of p53-deficient breast cancer benefited from the augmented direct cytotoxic effect and low risk of toxicities.
节拍化疗是指低剂量、频繁给予细胞毒药物而无停药间隙的治疗策略，它作为传统最大耐受剂量（MTD）疗法的替代方案，已在多项临床研究中显示出对乳腺癌患者的治疗益处。与 MTD 不同，节拍化疗通过多种机制发挥作用，包括抗血管生成作用和免疫调节作用，但由于剂量降低，其直接细胞毒性作用仅发挥次要作用。在 p53 缺失的乳腺癌范围内，我们通过联合使用 Chk1 抑制剂 MK-8776 来增强低剂量多柔比星的直接细胞毒性作用，从而证明了节拍化疗的增强抗癌作用。由于口服药物在节拍化疗中因其频繁和潜在的长期给药而受到极大的青睐，我们通过与脱氧胆酸形成离子复合物来制备口服多柔比星，当口服给予时，其显示出足够的生物利用度和抗癌作用。MK-8776 通过消除 Chk1 依赖性细胞周期阻滞，选择性增强低浓度多柔比星在 p53 缺失乳腺癌细胞中的细胞毒性作用。一致地，联合使用 MK-8776 可显著提高每日口服多柔比星在 p53 缺失乳腺癌异种移植模型中的抗癌作用，特别是在较低剂量的多柔比星下，且无明显的全身毒性。因此，MK-8776 和节拍口服多柔比星的联合治疗方案有望成为治疗 p53 缺失乳腺癌的一种有前途的方法，因为其增强了直接细胞毒性作用且毒性风险较低。
