In vivo anti-cancer efficacy of a hypoxia activated prodrug, TH-302.
Author: Wang, Jingli; Liu, Q; Rosario, G; McReynolds, C; Durnal, A; Evans, J; Ammons, S
Publisher: The Authors
Type: Conference item
Link to this item using this URL: http://hdl.handle.net/2292/18966
Background: A new hypoxia activated phosphoramidate prodrug, TH-302, was identified as a selective hypoxia targeted drug by in vitro screens. Using cell proliferation assays, TH-302 showed greater than 100 fold higher toxicity under anoxic conditions as compared to aerobic conditions across a broad range of cancer cell lines. In this study, we have tested the in vivo anti-cancer efficacy of TH-302 in different human cancer xenograft models. Method: H460-NCI human non-small-cell lung cancer cells, and HT29 human colon cancer cells, were implanted subcutaneously into the flanks of homozygous nude mice. Multiple doses of TH-302 with or without combination with chemotherapeutic agents were administrated when the tumor size reached 100 to 150 mm3. Animal body weight and tumor growth were measured for a maximum of 60 days after tumor implantation. TH-302 in vivo cell killing was also tested with an excision clonogenic assay. Results: Significant tumor growth inhibition was achieved in the H460 model by TH-302 monotherapy at different dose regimens when given IP: 50 mg/kg, QDx5/wkx2wk; 100 mg/kg, Q3Dx5; 150 mg/kg, Q7Dx3 or IP infusion for 14 days using Alzet osmotic pumps. The tumor growth inhibitions (TGIs) were 68%, 81%, 86% and 73% respectively. TH-302 also showed significant anti-cancer efficacy as a monotherapy agent in the HT29 model. Combining TH-302 with the chemotherapeutic agent Cisplatin (6 mg/kg, IV, Q7Dx2), resulted in increased anti-cancer efficacy as compared to Cisplatin alone in both models with 20% cure rate. In H460 model, TH-302 combined with Taxol also produced an increased anti-cancer efficacy than Taxol alone. To confirm the in vivo hypoxia targeted mechanism of TH-302, we performed an excision clonogenic assay. Animals were placed in chambers with different levels of oxygen (10%, 21% or 95% O2) for 2.5 hours before and after TH-302 administration. Tumors were excised 24 h later, and a clonogenic assay was performed to measure the in vivo cytoxicity. The results showed that TH-302 induced cell killing was O2 dependent with lower O2 levels associated with greater cytoxicity. Additionally, in the excision assay, greater than 99% of cells were killed in H460 tumors in vivo after a single dose (150mg/kg, IP) of TH-302 when the animals were breathing in air. These results suggest that the activated drug may kill cells outside of the hypoxic region, perhaps via a bystander effect, because hypoxic cells in H460 tumor were less than 99%. Conclusions: The hypoxic targeting agent TH-302 is clearly an effective anti-cancer agent either as a monotherapeutic agent or in combination with common chemotherapeutic agents in human cancer xenograft models. These results demonstrate that TH-302 should be tested in the treatment of solid tumors in human cancer patients.
Citation: ["AACR annual meeting, Los Angeles, USA, 14 Apr 2007 - 18 Apr 2007."]