Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: A novel antitumor agent?

Saltzman, Daniel A.; Katsanis, Emmanuel; Heise, Charles P.; Hasz, Diane E.; Вигдорович, В. И.; Kelly, Sandra M.; Curtiss, Roy; Leonard, Arnold S.; Anderson, Peter M.

doi:10.1016/s0022-3468(97)90198-6

Cited by 55 publications

(45 citation statements)

References 20 publications

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“…Individual drugs have been ineffective in treating pulmonary metastases [31], and combined therapy has not substantially altered the course of disease in patients who present with detectable pulmonary osteosarcoma metastases, as the 5-year survival rate continues to hover around 30% [9,11,37]. Our previous research demonstrates an antitumor effect in a variety of animal cancer models associated with oral dosing of attenuated Salmonella typhimurium with and without a truncated gene for human IL-2 [1,7,8,27,29,33]. This project represents the early assessment of S. typhimurium in an osteosarcoma pulmonary metastatic model.…”

Section: Discussionmentioning

confidence: 99%

“…We recently demonstrated a single oral dose of an attenuated Salmonella typhimurium genetically engineered with a gene for a truncated human interleukin-2 (SalpIL2) substantially reduces unresectable adenocarcinoma metastases to the liver in experimental treatment and prophylactic mouse models [7,8,27,29,33]. In addition, SalpIL2 reduces the volume and mass of retroperitoneal neuroblastoma tumors in an experimental murine treatment model [1].…”

Section: Introductionmentioning

confidence: 99%

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Attenuated Salmonella typhimurium with IL-2 Gene Reduces Pulmonary Metastases in Murine Osteosarcoma

Sorenson

Banton

Frykman

et al. 2008

Clinical Orthopaedics &Amp; Related Research

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Historically, osteosarcoma has been a problematic metastatic disease, with 40-80% of patients developing pulmonary metastasis after primary tumor resection. Recent treatment advancements have reduced the occurrence of metastatic lesions to less than 30%. Using attenuated Salmonella typhimurium, we previously demonstrated regression in tumor burden in murine solid tumor and metastatic models. We established a murine model for metastatic osteosarcoma to determine the effect of treatment with a single oral dose of attenuated S. typhimurium with (SalpIL2) and without (Sal-NG) a gene for a truncated human interleukin-2. Female balb/c mice were administered 2 9 10 5 (ATCC K7M2) osteosarcoma cells via tail vein injection from culture and treated by oral gavage of Salmonella species 3 days later. Mice were harvested for splenic lymphocytes and tumor enumeration by intratracheal injection with India ink 21 days after injection. Treatment with attenuated SalpIL2 reduced pulmonary metastases in number and volume compared to saline controls. Furthermore, splenic natural killer cell populations were increased 93% with SalpIL2 and 114% with Sal-NG compared to nontreated groups. This pulmonary metastasis model demonstrates attenuated Salmonella typhimurium with human interleukin-2 reduced metastatic osteosarcoma in mice and confirm the need for further investigation into the immunologic properties of SalpIL2 as a possible treatment for metastatic osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Attenuated Salmonella typhimurium with IL-2 Gene Reduces Pulmonary Metastases in Murine Osteosarcoma

Sorenson

Banton

Frykman

et al. 2008

Clinical Orthopaedics &Amp; Related Research

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“…The ability to genetically engineer Salmonella to secrete inflammatory or immunostimulatory cytokines at the tumor site represents a possible method for improving its antitumor efficacy although, it will depend on the fairly efficient infiltration of Salmonella throughout the growing tumor. Preliminary studies utilizing Salmonella typhimurium containing the human interleukin-2 gene were reported to improve the antitumor efficacy of Salmonella injection by stimulating natural killer and CD8 + cells (7).…”

Section: Discussionmentioning

confidence: 99%

“…In an attempt to increase the applicability of Salmonella organisms for cancer treatment, Salmonella typhimurium was genetically engineered to improve tumor targeting as well as to reduce toxicity (3)(4)(5)(6)(7). Chromosomal deletion of the purI gene creates a requirement for an external source of adenine, and deletion of the msbB gene prevents the addition of a terminal myristyl group to the lipid-A domain of lipopolysaccharide and thus, markedly diminishes its capacity to induce tumor necrosis factor-α production compared with the parental Salmonella.…”

mentioning

confidence: 99%

Antitumor Effects in Mice of the Intravenous Injection of Attenuated Salmonella Typhimurium

Rosenberg

Spiess

Kleiner

2002

Journal of Immunotherapy

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“…The tumor inhibition observed likely includes effects from the immune system, including CD8 + cytotoxic lymphocytes (Avogadri et al, 2005; Saltzman, 2005; Saltzman et al, 1997) and TGFα (Leschner et al, 2009). By comparing the studies in murine and canine systems with those in humans, it now appears that the antitumor effects in mice and dogs either do not occur or are insufficient to suppress tumor growth in humans.…”

Section: Introductionmentioning

confidence: 99%

EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

Quintero

Carrafa²,

Vincent³

et al. 2016

Biotech & Bioengineering

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Tumor-targeted Salmonella VNP20009 preferentially replicate within tumor tissue and partially suppress tumor growth in murine tumor models. These Salmonella have the ability to locally induce apoptosis when they are in direct contact with cancer cells but they lack significant bystander killing, which may correlate with their overall lack of antitumor activity in human clinical studies. In order to compensate for this deficiency without enhancing overall toxicity, we engineered the bacteria to express epidermal growth factor receptor (EGFR)-targeted cytotoxic proteins that are released into the extracellular milieu. In this study, we demonstrate the ability of the Salmonella strain VNP20009 to produce three different forms of the Pseudomonas exotoxin A (ToxA) chimeric with a tumor growth factor alpha (TGFα) which results in its producing culture supernatants that are cytotoxic and induce apoptosis in EGFR positive cancer cells as measured by the tetrazolium dye reduction, and Rhodamine 123 and JC-10 mitochondrial depolarization assays. In addition, exchange of the ToxA REDLK endoplasmic reticulum retention signal for KDEL and co-expression of the ColE3 lysis protein resulted in an overall increased cytotoxicity compared to the wild type toxin. This approach has the potential to significantly enhance the antitumor activity of VNP20009 while maintaining its previously established safety profile.

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Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: A novel antitumor agent?

Cited by 55 publications

References 20 publications

Attenuated Salmonella typhimurium with IL-2 Gene Reduces Pulmonary Metastases in Murine Osteosarcoma

Attenuated Salmonella typhimurium with IL-2 Gene Reduces Pulmonary Metastases in Murine Osteosarcoma

Antitumor Effects in Mice of the Intravenous Injection of Attenuated Salmonella Typhimurium

EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

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