Monotherapy with a Tumor-targeting Mutant of S. Typhimurium Inhibits Liver Metastasis in a Mouse Model of Pancreatic Cancer

Overview

Journal J Surg Res

Specialty General Surgery

Date 2009 Sep 22

PMID 19766244

Citations 81

Authors

Clinton Yam

Ming Zhao

Katsuhiro Hayashi

Huaiyu Ma

Hiroyuki Kishimoto

Michele McElroy

Michael Bouvet

Robert M Hoffman

Affiliations

Soon will be listed here.

Abstract

Cancer of the exocrine pancreas is the fourth leading cause of cancer deaths in the United States. Currently, surgical resection is the only hope for cure. The majority of patients present with locally-advanced or metastatic disease. The most common site for distant metastasis is the liver. We report here a modified auxotrophic strain of S. typhimurium that can target and inhibit the growth of liver metastasis in a mouse model of pancreatic cancer. This strain of S. typhimurium is auxotrophic (leucine-arginine dependent) but apparently receives sufficient nutritional support from tumor tissue. To increase tumor targeting ability and tumor killing efficacy, this strain was further modified by re-isolation from a tumor growing in a nude mouse and termed A1-R. In the present study, we demonstrate the efficacy of locally- as well as systemically-administered A1-R on liver metastasis of pancreatic cancer. Mice treated with A1-R given locally via intrasplenic injection or systemically via tail vein injection had a much lower hepatic and splenic tumor burden compared with control mice. Systemic treatment with intravenous A1-R also increased survival time. All results were statistically significant. This study suggests the clinical potential of bacterial treatment of a critical metastatic target of pancreatic cancer.

Citing Articles

Dynamic Fluorescence Imaging of Orally-administered Tumor-targeting A1-R Expressing Green Fluorescent Protein Trafficking Through the Gastrointestinal System to Target Fibrosarcomas in Nude Mice.

Morinaga S, Zhao M, Mizuta K, Kang B, Bouvet M, Yamamoto N In Vivo. 2025; 39(2):640-647.

PMID: 40010967 PMC: 11884439. DOI: 10.21873/invivo.13869.

The Combination of Tumor-targeting A1-R Plus the Autophagy-inhibitor Chloroquine Synergistically Eradicates HT1080 Fibrosarcoma Cells and .

Morinaga S, Zhao M, Mizuta K, Kang B, Bouvet M, Yamamoto N In Vivo. 2024; 39(1):102-109.

PMID: 39740880 PMC: 11705149. DOI: 10.21873/invivo.13807.

Accurate and Safe Tumor Targeting of Orally-administered A1-R Leads to Regression of an Aggressive Fibrosarcoma in Nude Mice.

Morinaga S, Zhao M, Mizuta K, Kang B, Sato M, Bouvet M In Vivo. 2024; 38(6):2601-2609.

PMID: 39477429 PMC: 11535920. DOI: 10.21873/invivo.13736.

Bactofection, Bacterial-Mediated Vaccination, and Cancer Therapy: Current Applications and Future Perspectives.

Renteria-Flores F, Garcia-Chagollan M, Jave-Suarez L Vaccines (Basel). 2024; 12(9).

PMID: 39340000 PMC: 11435753. DOI: 10.3390/vaccines12090968.

Bacterial derivatives mediated drug delivery in cancer therapy: a new generation strategy.

Ijaz M, Hasan I, Chaudhry T, Huang R, Zhang L, Hu Z J Nanobiotechnology. 2024; 22(1):510.

PMID: 39182109 PMC: 11344338. DOI: 10.1186/s12951-024-02786-w.

References

Yu Y, Timiryasova T, Zhang Q, Beltz R, Szalay A . Optical imaging: bacteria, viruses, and mammalian cells encoding light-emitting proteins reveal the locations of primary tumors and metastases in animals. Anal Bioanal Chem. 2003; 377(6):964-72. DOI: 10.1007/s00216-003-2065-0. View

Dang L, Bettegowda C, Huso D, Kinzler K, Vogelstein B . Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Natl Acad Sci U S A. 2001; 98(26):15155-60. PMC: 64999. DOI: 10.1073/pnas.251543698. View

Mengesha A, Dubois L, Lambin P, Landuyt W, Chiu R, Wouters B . Development of a flexible and potent hypoxia-inducible promoter for tumor-targeted gene expression in attenuated Salmonella. Cancer Biol Ther. 2006; 5(9):1120-8. DOI: 10.4161/cbt.5.9.2951. View

Fox M, Lemmon M, Mauchline M, Davis T, Giaccia A, Minton N . Anaerobic bacteria as a delivery system for cancer gene therapy: in vitro activation of 5-fluorocytosine by genetically engineered clostridia. Gene Ther. 1996; 3(2):173-8. View

Pawelek J, Low K, Bermudes D . Tumor-targeted Salmonella as a novel anticancer vector. Cancer Res. 1997; 57(20):4537-44. View

Clairmont C, Lee K, Pike J, Ittensohn M, Low K, Pawelek J . Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium. J Infect Dis. 2000; 181(6):1996-2002. DOI: 10.1086/315497. View

Kimura N, Taniguchi S, Aoki K, Baba T . Selective localization and growth of Bifidobacterium bifidum in mouse tumors following intravenous administration. Cancer Res. 1980; 40(6):2061-8. View

Yu Y, Shabahang S, Timiryasova T, Zhang Q, Beltz R, Gentschev I . Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nat Biotechnol. 2004; 22(3):313-20. DOI: 10.1038/nbt937. View

Brown J, Giaccia A . The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 1998; 58(7):1408-16. View

10.

Zhao M, Geller J, Ma H, Yang M, Penman S, Hoffman R . Monotherapy with a tumor-targeting mutant of Salmonella typhimurium cures orthotopic metastatic mouse models of human prostate cancer. Proc Natl Acad Sci U S A. 2007; 104(24):10170-4. PMC: 1891231. DOI: 10.1073/pnas.0703867104. View

11.

Zhao M, Yang M, Li X, Jiang P, Baranov E, Li S . Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc Natl Acad Sci U S A. 2005; 102(3):755-60. PMC: 545558. DOI: 10.1073/pnas.0408422102. View

12.

Tsuji K, Yang M, Jiang P, Maitra A, Kaushal S, Yamauchi K . Common bile duct injection as a novel method for establishing red fluorescent protein (RFP)-expressing human pancreatic cancer in nude mice. JOP. 2006; 7(2):193-9. View

13.

Zhao M, Yang M, Ma H, Li X, Tan X, Li S . Targeted therapy with a Salmonella typhimurium leucine-arginine auxotroph cures orthotopic human breast tumors in nude mice. Cancer Res. 2006; 66(15):7647-52. DOI: 10.1158/0008-5472.CAN-06-0716. View

14.

GERICKE D, ENGELBART K . ONCOLYSIS BY CLOSTRIDIA. II. EXPERIMENTS ON A TUMOR SPECTRUM WITH A VARIETY OF CLOSTRIDIA IN COMBINATION WITH HEAVY METAL. Cancer Res. 1964; 24:217-21. View

15.

Yazawa K, Fujimori M, Nakamura T, Sasaki T, Amano J, Kano Y . Bifidobacterium longum as a delivery system for gene therapy of chemically induced rat mammary tumors. Breast Cancer Res Treat. 2001; 66(2):165-70. DOI: 10.1023/a:1010644217648. View

16.

Malmgren R, FLANIGAN C . Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration. Cancer Res. 1955; 15(7):473-8. View

17.

Hoiseth S, Stocker B . Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature. 1981; 291(5812):238-9. DOI: 10.1038/291238a0. View

18.

Yazawa K, Fujimori M, Amano J, Kano Y, Taniguchi S . Bifidobacterium longum as a delivery system for cancer gene therapy: selective localization and growth in hypoxic tumors. Cancer Gene Ther. 2000; 7(2):269-74. DOI: 10.1038/sj.cgt.7700122. View

19.

Low K, Ittensohn M, Le T, Platt J, Sodi S, Amoss M . Lipid A mutant Salmonella with suppressed virulence and TNFalpha induction retain tumor-targeting in vivo. Nat Biotechnol. 1999; 17(1):37-41. DOI: 10.1038/5205. View

20.

Toso J, Gill V, Hwu P, Marincola F, Restifo N, Schwartzentruber D . Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol. 2002; 20(1):142-52. PMC: 2064865. DOI: 10.1200/JCO.2002.20.1.142. View