Abstract
ObjectiveIncreasing 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.MethodsMice 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.ResultsRGD-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.ConclusionsThese results suggest that targeted delivery of low doses of RGD-rmhTNF-α into the tumor vasculature increases the antitumor efficacy of chemotherapeutic drugs.
Highlights
Tumor necrosis factor-a (TNF-a) exhibits potent antitumor activity, alters endothelial barrier function, reduces tumor interstitial pressure, and mediates immune responses [1]
When combined with the traditional chemotherapeutic drug doxorubicin, RGD-rmhTNF-a increased intratumoral doxorubicin levels and synergized with doxorubicin to enhance the antitumor activity of this chemotherapy. These results suggested that targeted delivery of low doses of RGD-rmhTNF-a to the tumor vasculature increased the therapeutic efficacy of chemotherapeutic drugs for solid tumors
We tested whether RGD-rmhTNF-a could increase the entry of a chemotherapeutic agent into the tumor and found that co-administration of RGDrmhTNF-a with doxorubicin increased the intratumoral levels of doxorubicin compared to doxorubicin treatment alone
Summary
Tumor necrosis factor-a (TNF-a) exhibits potent antitumor activity, alters endothelial barrier function, reduces tumor interstitial pressure, and mediates immune responses [1]. Systemic TNF-a administration for antitumor therapy is accompanied by prohibitive toxicity, where the maximum tolerated dose (8–10 mg/kg) is 10 to 50 times lower than the estimated effective dose [2,3,4] For this reason, systemic TNF-a administration has been abandoned as a viable therapy, and its clinical use has been limited to locoregional treatments [5,6]. Systemic TNF-a administration has been abandoned as a viable therapy, and its clinical use has been limited to locoregional treatments [5,6] To overcome this limitation of toxicity, an effort has been made to create a TNF mutant by protein-engineering methods that retains the antitumor ability of TNF-a but exhibits decreased toxicity [7,8,9]. We previously reported that rmhTNF-a treatment increased antitumor activity with reduced toxicity in H22 hepatoma and S180 sarcoma allografted mice [10]
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