51. Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model
- Author
-
Kawaguchi, Kei, Igarashi, Kentaro, Murakami, Takashi, Chmielowski, Bartosz, Kiyuna, Tasuku, Zhao, Ming, Zhang, Yong, Singh, Arun, Unno, Michiaki, Nelson, Scott D, Russell, Tara A, Dry, Sarah M, Li, Yunfeng, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Brain Disorders ,Cancer ,Aged ,Animals ,Antineoplastic Agents ,Alkylating ,Dacarbazine ,Female ,Humans ,Melanoma ,Mice ,Mice ,Nude ,Mutation ,Proto-Oncogene Proteins B-raf ,Salmonella typhimurium ,Temozolomide ,Xenograft Model Antitumor Assays ,melanoma ,PDOX ,nude mice ,orthotopic ,drug-response ,Oncology and Carcinogenesis - Abstract
Melanoma is a recalcitrant disease in need of transformative therapuetics. The present study used a patient-derived orthotopic xenograft (PDOX) nude-mouse model of melanoma with a BRAF-V600E mutation to determine the efficacy of temozolomide (TEM) combined with tumor-targeting Salmonella typhimurium A1-R. A melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 40 PDOX nude mice were divided into 4 groups: G1, control without treatment (n = 10); G2, TEM (25 mg/kg, administrated orally daily for 14 consecutive days, n = 10); G3, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); G4, TEM combined with S. typhimurium A1-R (25 mg/kg, administrated orally daily for 14 consecutive days and 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, respectively, n = 10). Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, all treatments significantly inhibited tumor growth compared to untreated control (TEM: p < 0.0001; S. typhimurium A1-R: p < 0.0001; TEM combined with S. typhimurium A1-R: p < 0.0001). TEM combined with S. typhimurium A1-R was significantly more effective than either S. typhimurium A1-R (p = 0.0004) alone or TEM alone (p = 0.0017). TEM combined with S. typhimurium A1-R could regress the melanoma in the PDOX model and has important future clinical potential for melanoma patients.
- Published
- 2016