1 University of Texas Health Science Center McGovern Medical School at Houston, Houston, TX, USA.
2 UTHealth-Memorial Hermann Cancer Center-TMC, Houston, TX, USA.
Integr Cancer Ther. 2018 Sep;17(3):755-761. doi: 10.1177/1534735417740631. Epub 2017 Nov 20.
To determine the activity of fucoidan from Undaria pinnatifida (UPF) and Fucus vesiculosus (FVF) when given in combination of chemotherapy drugs using selected human breast or ovarian cancer orthotopic mouse models.
Mice were inoculated with 1 × 10 cells of TOV-112d, MCF-7, or ZR-75 subcutaneously or SKOV-GFP-Luc intraperitoneally on day 0. MCF-7 and ZR-75 mice were administered with estradiol valerate 2 mg/kg in 0.2 mL castor oil subcutaneously two days prior to cell inoculation. Mice were randomized to one of six arms (N = 10/arm) paclitaxel, UPF/paclitaxel, FVF/paclitaxel, tamoxifen, UPF/tamoxifen, or FVF/tamoxifen. Tumors were measured three times per week for 28 days.
Improved activity was observed with UPF or FVF in combination with tamoxifen in both the MCF-7 and ZR-75D breast cancer mouse models. Decreased activity of paclitaxel was observed when given in combination with UPF or FVF in both breast cancer mouse models. The combination of FVF/tamoxifen in the TOV-112d ovarian cancer mouse model had improved activity but no there was difference observed with the UPF/tamoxifen in either ovarian cancer mouse model. No difference was observed with combination of UPF or FVF with paclitaxel in human ovarian cancer SKOV or TOV-112d orthotopic mouse models.
This study did confirm that UPF/FVF in combination with tamoxifen did not decrease tamoxifen activity in both breast and ovarian cancer, with some potential to improve activity compared to tamoxifen alone in breast cancers. Previous in vitro studies had suggested UPF and FVF had overall synergistic activity with paclitaxel; however, in the current in vivo human cancer mouse model studies there was no change in paclitaxel activity when given in combination with UPF or FVF in either of the two human ovarian cancer models. Furthermore, this study demonstrated that UPF or FVF given in combination with paclitaxel had a potential antagonistic effect in breast cancer models. Additional studies are warranted to delineate mechanisms contributing to variation in the in vivo activity when given in combination with paclitaxel. As a first step, a clinical pharmacokinetic study evaluating impact of FVF/UPF given in combination with chemotherapy in patients with solid tumors is underway.
在选定的人乳腺癌或卵巢癌原位动物模型中，通过联合化疗药物，确定来自裙带菜（UPF）和泡叶藻（FVF）的褐藻糖胶的活性。
将 1×10 的 TOV-112d、MCF-7 或 ZR-75 细胞皮下接种或 SKOV-GFP-Luc 细胞腹腔内接种于小鼠，MCF-7 和 ZR-75 小鼠在细胞接种前 2 天皮下给予 2 毫克/千克雌二醇戊酸酯在 0.2 毫升蓖麻油中。将小鼠随机分为六组（每组 10 只/组）：紫杉醇、UPF/紫杉醇、FVF/紫杉醇、他莫昔芬、UPF/他莫昔芬或 FVF/他莫昔芬。28 天内每周测量肿瘤 3 次。
在 MCF-7 和 ZR-75D 乳腺癌小鼠模型中，与紫杉醇联合使用 UPF 或 FVF 观察到活性增强。在两种乳腺癌小鼠模型中，与紫杉醇联合使用 UPF 或 FVF 时，紫杉醇的活性降低。在 TOV-112d 卵巢癌小鼠模型中，FVF/他莫昔芬联合用药具有增强的活性，但在两种卵巢癌小鼠模型中均未观察到 UPF/他莫昔芬的差异。在人卵巢癌 SKOV 或 TOV-112d 原位小鼠模型中，联合使用 UPF 或 FVF 与紫杉醇无差异。
本研究证实 UPF/FVF 联合他莫昔芬不会降低他莫昔芬在乳腺癌和卵巢癌中的活性，与单独使用他莫昔芬相比，在乳腺癌中具有增强活性的潜力。先前的体外研究表明 UPF 和 FVF 与紫杉醇具有总体协同活性；然而，在当前的人卵巢癌原位动物模型研究中，当与 UPF 或 FVF 联合使用时，紫杉醇的活性没有变化。此外，本研究表明，在乳腺癌模型中，与紫杉醇联合使用 UPF 或 FVF 可能具有拮抗作用。需要进一步的研究来阐明与紫杉醇联合使用时体内活性变化的机制。作为第一步，正在进行一项临床药代动力学研究，评估在实体瘤患者中联合使用 FVF/UPF 对化疗的影响。
