Abstract 3342: Combining Pemetrexed with methoxyamine to enhance the radiosensitization of non-small-cell lung cancer (NSCLC): Preclinical studies in vivo

Abstract

Abstract Combining Pemetrexed with Methoxyamine to Enhance the Radiosensitization of Non-Small-Cell Lung Cancer (NSCLC): Preclinical Studies in vivo BACKGROUND: Stage III lung cancer is often treated with radiation therapy (RT) and a platin, and recent clinical trials have found benefit for tumors of non-squamous histology of adding Pemetrexed on stage IV disease. Since the cytotoxic effects of Pemetrexed are amplified in the presence of methoxyamine, we tested the ability of methoxyamine to also amplify the radiosensitization provided by Pemetrexed. METHODS: Human lung cancer cells (A549, expressing wild-type p53, or H1299, p53 null) were inoculated into the right flank of female athymic nude mice. When the xenografts reached 100-175 mm3, the mice were randomized (Day 0) into 4 arms, which were given 5 daily doses (Days 1-5) of Pemetrexed (150 mg/kg) and/or methoxyamine (4 mg/kg) or no drugs. On Day 6, half of the tumors of each arm were irradiated (8 Gy single fraction, Cs-137 γ-radiation). Twice weekly the animals were weighed and tumor growth was monitored by calipers. RESULTS: None of the treatments caused animals to lose weight. For A549 xenografts, growth rates for all treatment arms differed significantly from the untreated control growth rate (p<0.0001); tumors treated with Pemetrexed/methoxyamine/RT grew at the slowest rate (8 mm3/day), which was significantly slower than that for RT alone (18 mm3/day), methoxyamine/RT (19.3 mm3/day), or Pemetrexed/RT (15 mm3/day) (p<0.0001). Similar differences in growth rate were found for the H1299 xenografts. The data were also analyzed as the time for the volume of A549 xenografts to reach 400 mm3 or H1299 xenografts to reach 600 mm3. For A549, the median time for the Pemetrexed/methoxyamine/RT arm (38 days) was greater than those produced by no treatment (14 days with 2 cures; p<0.0001), RT alone (21 days with 1 cure; p = 0.05) and Pemetrexed/RT (26 days with no cures; p = 0.055). For H1299, a similar ranking of time-to-endpoint was found. Based on our studies of the two cell lines in vitro, it appears that the radiosensitizing effect of Pemetrexed + methoxyamine results from cell cycle redistribution to the G1/S border and early S-phase along with inhibition of DNA damage repair. CONCLUSIONS: The addition of methoxyamine to the pre-irradiation treatment of A549 and H1299 xenografts significantly reduced the tumor growth rate after RT and extended the tumor growth delay. Since methoxyamine enhanced the radiosensitization by Pemetrexed in both tumor types, p53 is not necessary for this response. Note: This abstract was not presented at the meeting. Citation Format: Ravi Patel, Rutul Patel, Tithi Biswas, Pingfu Fu, Mitchell Machtay, Nancy Oleinick. Combining Pemetrexed with methoxyamine to enhance the radiosensitization of non-small-cell lung cancer (NSCLC): Preclinical studies in vivo . [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3342. doi:10.1158/1538-7445.AM2015-3342