Denslow Agnieszka, Switalska Marta, Nowak Marcin, Maciejewska Magdalena, Chlopicki Stefan, Marcinek Andrzej, Gebicki Jerzy, Wietrzyk Joanna
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, Wroclaw, 53-114, Poland.
Wroclaw University of Environmental and Life Sciences, Norwida 31, Wroclaw, 50-375, Poland.
BMC Cancer. 2017 Mar 7;17(1):177. doi: 10.1186/s12885-017-3161-4.
We previously showed that 1-methylnicotinamide (1-MNA) and its analog 1,4-dimethylpyridine (1,4-DMP) could inhibit the formation of lung metastases and enhance the efficacy of cyclophosphamide-based chemotherapy in the model of spontaneously metastasizing 4T1 mouse mammary gland tumors. In the present study, we aimed to investigate whether the previously observed activity of pyridine compounds pertains also to the prevention and the treatment of metastatic prostate tumors, in a combined chemotherapy with docetaxel.
Cancer-preventing activity of 1,4-DMP was studied in the model of prostate tumors spontaneously arising in C57BL/6-Tg (TRAMP)8247Ng/J (TRAMP) mice. The efficacy of the combined chemotherapy, comprising simultaneous use of 1,4-DMP and docetaxel, was evaluated in the orthotopic mouse model of human PC-3M-luc2 prostate cancer. The toxicity of the applied treatment was also determined.
The development of prostate tumors in TRAMP mice remained unaffected after administration of 1,4-DMP. Similarly, no effect of 1,4-DMP was found on the growth of orthotopically transplanted PC-3M-luc2 tumors. However, when 1,4-DMP was administered along with docetaxel, it enhanced the anticancer activity of the chemotherapy. As a result, in PC-3M-luc2-bearing mice statistically significant inhibition of the tumor growth and lower metastases incidence were observed. The decreased metastatic yield is probably related to the diminished platelet activity observed in mice treated with combined therapeutic regimen. Finally, the combined treatment exhibited lowered side effects accompanying docetaxel administration.
Results presented herein confirm previously published data on the anticancer activity of pyridine compounds and demonstrate that 1,4-DMP may be beneficially implemented into chemotherapy utilizing various cytotoxic agents, directed against multiple metastatic tumor types.
我们之前的研究表明，在自发转移的4T1小鼠乳腺肿瘤模型中，1-甲基烟酰胺（1-MNA）及其类似物1,4-二甲基吡啶（1,4-DMP）可抑制肺转移的形成，并增强基于环磷酰胺的化疗效果。在本研究中，我们旨在探讨吡啶化合物先前观察到的活性是否也适用于多西他赛联合化疗中转移性前列腺肿瘤的预防和治疗。
在C57BL/6-Tg（TRAMP）8247Ng/J（TRAMP）小鼠自发产生前列腺肿瘤的模型中研究1,4-DMP的防癌活性。在人PC-3M-luc2前列腺癌原位小鼠模型中评估1,4-DMP与多西他赛同时使用的联合化疗效果。还测定了所用治疗的毒性。
给予1,4-DMP后，TRAMP小鼠前列腺肿瘤的发生未受影响。同样，未发现1,4-DMP对原位移植的PC-3M-luc2肿瘤生长有影响。然而，当1,4-DMP与多西他赛一起给药时，它增强了化疗的抗癌活性。结果，在携带PC-3M-luc2的小鼠中观察到肿瘤生长受到统计学上显著的抑制，转移发生率降低。转移率降低可能与联合治疗方案处理的小鼠中观察到的血小板活性降低有关。最后，联合治疗显示出多西他赛给药时伴随的副作用降低。
本文给出的结果证实了先前发表的关于吡啶化合物抗癌活性的数据，并表明1,4-DMP可有益地应用于利用各种细胞毒性药物针对多种转移性肿瘤类型的化疗中。
