Systemic administration of attenuated Salmonella choleraesuis in combination with cisplatin for cancer therapy

• Published in: Molecular therapy Vol. 11; no. 5; pp. 707 - 716
• Main Authors: Lee, Che-Hsin, Wu, Chao-Liang, Tai, Yun-Sheng, Shiau, Ai-Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2005; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; cancer therapy; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; cisplatin; Cisplatin - administration & dosage; Cisplatin - therapeutic use; combination therapy; hypoxia; Hypoxia - microbiology; Hypoxia - pathology; Leukocyte Count; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasms - immunology; Neoplasms - microbiology; Neoplasms - pathology; Neoplasms - therapy; Neutrophils - cytology; Neutrophils - immunology; Salmonella; Salmonella - physiology; Salmonella choleraesuis; Survival Rate; tumor targeted; Xenograft Model Antitumor Assays; cancer therapy; hypoxia; tumor targeted; combination therapy; cisplatin; Salmonella choleraesuis
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2005.01.008

Some anaerobic and facultative anaerobic bacteria have been employed as anticancer agents. Previously, we have demonstrated tumor-targeting and antitumor activities of attenuated Salmonella choleraesuis carrying antiangiogenic genes. Here we exploited S. choleraesuis as a single-agent therapy and as part of a combination therapy with low-dose cisplatin for syngeneic murine lung tumor and hepatoma. Systemically injected S. choleraesuis preferentially accumulated within tumors for at least 4 weeks and the bacteria accumulated preferentially in not only subcutaneous but also orthotopic tumors over livers and spleens at ratios ranging from 1000:1 to 100,000:1. S. choleraesuis was capable of delaying tumor growth and enhancing survival in both subcutaneous tumor and experimental metastasis models. More strikingly, the combination of S. choleraesuis plus cisplatin acted additively to retard tumor growth and extensively prolong the survival time of the mice bearing hepatomas or lung tumors. Such combination treatment also increased infiltrating neutrophils and CD8+ T cells, as well as apoptotic cells, in the tumors, compared with S. choleraesuis or cisplatin treatment alone. These findings suggest that S. choleraesuis in combination with cisplatin, which exerts oncolytic effects and enhances antitumor immune responses, represents a promising strategy for the treatment of primary and metastatic tumors.