Anti-tumor activity of an immunotoxin (TGFα-PE38) delivered by attenuated Salmonella typhimurium

Kawaguchi

et al. 2018

Heliyon

Gastrointestinal stromal tumor (GIST) is a refractory disease in need of novel efficacious therapy. The aim of our study was to evaluate the effectiveness of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) using on a patient derived orthotopic xenograft (PDOX) model of imatinib-resistant GIST. The GIST was obtained from a patient with regional recurrence, and implanted in the anterior gastric wall of nude mice. The GIST PDOX mice were randomized into 3 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration [p.o.], daily, for 3 weeks); G3, S. typhimurium A1-R group (intravenous [i.v.] injection, weekly, for 3 weeks). All mice from each group were sacrificed on day 22. Relative tumor volume was estimated by laparotomy on day 0 and day 22. Body weight of the mouse was evaluated 2 times per week. We found that S. typhimurium A1-R significantly reduced tumor growth in contrast to the untreated group (P = 0.001). In addition, we found that S. typhimurium A1-R was more effective compared to imatinib (P = 0.013). Furthermore, Imatinib was not significantly effective compared to the control group (P = 0.462). These results indicate that S. typhimurium A1-R may be new effective therapy for imatinib-resistant GIST and therefore a good candidate for clinical development of this disease.

Section: Discussionmentioning

confidence: 99%

Tumor-targeting Salmonella typhimurium A1-R suppressed an imatinib-resistant gastrointestinal stromal tumor with c-kit exon 11 and 17 mutations

Kawaguchi

et al. 2018

Heliyon

“…The released TGFα-PE38 was then tested in mice with implanted colon or breast tumor cells, which expressed high levels of EGFR (epidermal growth factor receptor). Lower solid tumor growth rate was shown comparing to just intracerebral infusion of TGFα-PE38 [97].…”

Section: Engineering Of Rips For Improving the Anti-cancer Efficacymentioning

confidence: 92%

Engineering of Ribosome-inactivating Proteins for Improving Pharmacological Properties

Lü

Zhu

Zheng

et al. 2020

Toxins

Ribosome-inactivating proteins (RIPs) are N-glycosidases, which depurinate a specific adenine residue in the conserved α-sarcin/ricin loop (α-SRL) of rRNA. This loop is important for anchoring elongation factor (EF-G for prokaryote or eEF2 for eukaryote) in mRNA translocation. Translation is inhibited after the attack. RIPs therefore may have been applied for anti-cancer, and anti-virus and other therapeutic applications. The main obstacles of treatment with RIPs include short plasma half-life, non-selective cytotoxicity and antigenicity. This review focuses on the strategies used to improve the pharmacological properties of RIPs on human immunodeficiency virus (HIV) and cancers. Coupling with polyethylene glycol (PEG) increases plasma time and reduces antigenicity. RIPs conjugated with antibodies to form immunotoxins increase the selective toxicity to target cells. The prospects for future development on the engineering of RIPs for improving their pharmacological properties are also discussed.

“…The bacteria Clostridium botulinum produces Botulinum neurotoxin A, which diminishes cell proliferation in prostate cancer (PC-3 and LNCaP) [ 18 ] and induces apoptosis in breast cancer cell lines (T47D) [ 19 , 20 ]. In another study by Lim et al, modified Pseudomonas exotoxin A (PE38), a natural ligand of epidermal growth factor receptor (EGFR) when expressed in Salmonella typhimurium , led to the inhibition of the solid tumor growth in mice implanted with colon cancer cells and 4T1 breast cancer cells having considerable EGFR expression [ 21 ].…”

Section: Mechanism Of Tumor Suppressionmentioning

confidence: 99%

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

Sawant

Patil

Gupta

et al. 2020

IJMS

Conventional anti-cancer therapy involves the use of chemical chemotherapeutics and radiation and are often non-specific in action. The development of drug resistance and the inability of the drug to penetrate the tumor cells has been a major pitfall in current treatment. This has led to the investigation of alternative anti-tumor therapeutics possessing greater specificity and efficacy. There is a significant interest in exploring the use of microbes as potential anti-cancer medicines. The inherent tropism of the bacteria for hypoxic tumor environment and its ability to be genetically engineered as a vector for gene and drug therapy has led to the development of bacteria as a potential weapon against cancer. In this review, we will introduce bacterial anti-cancer therapy with an emphasis on the various mechanisms involved in tumor targeting and tumor suppression. The bacteriotherapy approaches in conjunction with the conventional cancer therapy can be effective in designing novel cancer therapies. We focus on the current progress achieved in bacterial cancer therapies that show potential in advancing existing cancer treatment options and help attain positive clinical outcomes with minimal systemic side-effects.