Tumor vasculature-targeted recombinant mutated human TNF-α enhanced the antitumor activity of doxorubicin by increasing tumor vessel permeability in mouse xenograft models.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These results suggest that targeted delivery of low doses of RGD-rmhTNF-α into the tumor vasculature increases the antitumor efficacy of chemotherapeutic drugs.
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.
Changli
C
Jiang
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Junzhou
J
Niu
The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China.
Meng
M
Li
Clinical Laboratory, Army Center for Molecular Biological Analysis, Kunming General Hospital of Chengdu Military Area, Kunming, Yunnna, China.
Yi
Y
Teng
Clinical Laboratory, Army Center for Molecular Biological Analysis, Kunming General Hospital of Chengdu Military Area, Kunming, Yunnna, China.
Huixuan
H
Wang
The State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China.
Yingqi
Y
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000503:physiopathology; D004317:Doxorubicin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005070:Evans Blue; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D005070:Evans Blue; D004317:Doxorubicin