Jiang Changli, Niu Junzhou, Li Meng, Teng Yi, Wang Huixuan, Zhang Yingqi
Clinical Laboratory, Army Center for Molecular Biological Analysis, Kunming General Hospital of Chengdu Military Area, Kunming, Yunnna, China ; The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China.
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
PLoS One. 2014 Jan 22;9(1):e87036. doi: 10.1371/journal.pone.0087036. eCollection 2014.
Increasing evidence suggests that, when used in combination, tumor necrosis factor-α (TNF-α) synergizes with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant mutated human TNF-α specifically targeted to the tumor vasculature (RGD-rmhTNF-α) combined with the chemotherapeutic agent doxorubicin in 2 murine allografted tumor models.
Mice bearing hepatoma or sarcoma allografted tumors were treated with various doses of RGD-rmhTNF-α alone or in combination with doxorubicin (2 mg/kg). We then evaluated tumor growth and tumor vessel permeability as well as intratumoral levels of RGD-rmhTNF-α and doxorubicin.
RGD-rmhTNF-α treatment enhanced the permeability of the tumor vessels and increased intratumoral doxorubicin levels. In addition, intratumoral RGD-rmhTNF-α levels were significantly higher than that of rmhTNF-α. In both of the tested tumor models, administering RGD-rmhTNF-α in combination with doxorubicin resulted in an enhanced antitumor response compared to either treatment alone. Double-agent combination treatment of doxorubicin with 50,000 IU/kg RGD-rmhTNF-α induced stronger antitumor effects on H22 allografted tumor-bearing mice than the single doxorubicin agent alone. Moreover, doxorubicin with 10,000 IU/kg RGD-rmhTNF-α synergized to inhibit tumor growth in S180 allografted tumor-bearing mice.
These results suggest that targeted delivery of low doses of RGD-rmhTNF-α into the tumor vasculature increases the antitumor efficacy of chemotherapeutic drugs.
越来越多的证据表明，肿瘤坏死因子-α（TNF-α）与传统化疗药物联合使用时，会协同发挥更强的抗肿瘤作用。本研究在两种小鼠同种异体移植肿瘤模型中，研究了特异性靶向肿瘤血管的重组突变型人TNF-α（RGD-rmhTNF-α）与化疗药物阿霉素联合使用的抗肿瘤疗效。
对携带肝癌或肉瘤同种异体移植肿瘤的小鼠，单独给予不同剂量的RGD-rmhTNF-α，或与阿霉素（2mg/kg）联合使用。然后我们评估了肿瘤生长、肿瘤血管通透性以及肿瘤内RGD-rmhTNF-α和阿霉素的水平。
RGD-rmhTNF-α治疗增强了肿瘤血管的通透性，并提高了肿瘤内阿霉素水平。此外，肿瘤内RGD-rmhTNF-α水平显著高于rmhTNF-α。在两种测试的肿瘤模型中，与单独使用任何一种治疗相比，联合使用RGD-rmhTNF-α和阿霉素均导致抗肿瘤反应增强。阿霉素与50,000IU/kg RGD-rmhTNF-α的双药联合治疗对H22同种异体移植荷瘤小鼠的抗肿瘤作用比单独使用阿霉素更强。此外，阿霉素与10,000IU/kg RGD-rmhTNF-α协同抑制S180同种异体移植荷瘤小鼠的肿瘤生长。
这些结果表明，将低剂量的RGD-rmhTNF-α靶向递送至肿瘤血管可提高化疗药物的抗肿瘤疗效。
