期刊
MOLECULAR CANCER THERAPEUTICS
卷 5, 期 1, 页码 89-96出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-05-0163
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- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000929, Z01AI000929] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [ZIADE000699] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [Z01DE000699] Funding Source: NIH RePORTER
Previously, we have generated a potent prodrug consisting of modified anthrax toxins that is activated by urokinase plasminogen activator (uPA). The cytotoxicity of the drug, PrAg-U2+FP59, is dependent on the presence of receptor-associated uPA activity. Local intradermal administration of PrAg-U2+FP59 adjacent to the tumor nodules in mice with transplanted solid tumors had a potent antitumor effect. In succession of these experiments, we have now investigated the systemic antitumor efficacy of PrAg-U2+FP59. C57BI/6J mice bearing syngenic tumors derived from B16 melanoma, T241 fibrosarcoma, or Lewis lung carcinoma cells were treated with different mass ratios and doses of PrAg-U2+FP59. Tumor volumes were recorded daily by caliper measurements. In some experiments, dexamethasone was coadministered. Our data show a significant antitumor effect of systemic administration of PrAg-U2+FP59 in three syngenic tumor models. Optimal antitumor effect and low toxicity was obtained with a 25:1 mass ratio between the two components (PrAg-U2 and FP59). The experiments show that PrAg-U2+FP59 displays a clear dose-response relationship with regard to both antitumor efficacy and systemic toxicity. Dose-limiting toxicity seemed to be due to activation of the prodrug by uPA and its receptor in the intestinal mucosa. Concurrent treatment with dexamethasone was found to prevent dose-limiting toxicity. Taken together, these data indicate that uPA-activated toxins may be promising candidates for targeted therapy of human cancers that overexpress uPA and its receptor.
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