Cubides-Cely Sebastian, David Castro Alexander, Prado-Guevara Pablo, Mantilla-Hernández Julio César, Negrette-Guzmán Mario
Pharmacology and Metabolism Research Laboratory, Universidad Industrial de Santander, Bucaramanga 68002, Colombia.
Department of Pathology, Universidad Industrial de Santander, Bucaramanga 68002, Colombia.
Int J Mol Sci. 2025 Jun 19;26(12):5859. doi: 10.3390/ijms26125859.
Docetaxel is extensively used for treating different types of cancer; however, its clinical efficacy is primarily limited by myelotoxicity and peripheral neuropathy, adverse effects that often lead to treatment discontinuation. This study aimed to establish a preclinical model in Wistar rats for the simultaneous induction of myelotoxicity and peripheral neuropathy associated with docetaxel administration, enabling the evaluation of potential chemopreventive agents. Four distinct docetaxel administration schemes were assessed by performing behavioral nociceptive tests and complete blood cell counts. After establishing the damage model (5 mg/kg/week docetaxel for six weeks), we co-administered 100 mg/kg/week oral dimethyl fumarate to assess its protective effect. Dimethyl fumarate attenuated docetaxel-induced hyperalgesia, likely through preserving normal nerve fiber density in sciatic nerves, but neutropenia was not significantly mitigated. An alternative regimen with additional pre-administered doses of dimethyl fumarate showed a trend toward neutropenia attenuation and suggested an interesting inhibition of docetaxel-induced rat vibrissae loss. Chou-Talalay isobolographic analyses on prostate cancer cell lines revealed that dimethyl fumarate does not impair the therapeutic effect of docetaxel at most combination ratios evaluated; rather, synergistic effects were observed. This experimental model proved useful and will facilitate further research into the protective role of dimethyl fumarate and other potential chemoprotective agents.
多西他赛被广泛用于治疗不同类型的癌症；然而，其临床疗效主要受骨髓毒性和周围神经病变的限制，这些不良反应常常导致治疗中断。本研究旨在建立一个Wistar大鼠的临床前模型，用于同时诱导与多西他赛给药相关的骨髓毒性和周围神经病变，从而能够评估潜在的化学预防剂。通过进行行为伤害感受测试和全血细胞计数，评估了四种不同的多西他赛给药方案。在建立损伤模型（每周5mg/kg多西他赛，共六周）后，我们联合给予100mg/kg/周的口服富马酸二甲酯，以评估其保护作用。富马酸二甲酯减轻了多西他赛诱导的痛觉过敏，可能是通过维持坐骨神经中正常的神经纤维密度，但中性粒细胞减少症并未得到显著缓解。一种额外预先给予富马酸二甲酯剂量的替代方案显示出中性粒细胞减少症减轻的趋势，并提示对多西他赛诱导的大鼠触须脱落有有趣的抑制作用。对前列腺癌细胞系进行的Chou-Talalay等效线图分析表明，在评估的大多数组合比例下，富马酸二甲酯不会损害多西他赛的治疗效果；相反，观察到了协同作用。该实验模型被证明是有用的，将有助于进一步研究富马酸二甲酯和其他潜在化学保护剂的保护作用。
