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Bacteria and Bioactive Peptides
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Ameer Khusro, Chirom Aarti, Paul Agastian
The live, attenuated, or genetically modified, nonpathogenic bacteria or their tumoricidal constituents emerged as potent antitumor agents for the treatment of this disease. Later studies used pathogenic species of the anaerobic clostridia for their proliferation within the necrotic (anaerobic) regions of tumors in experimental animals as compared to normal tissues. The experiments caused regression of tumors but showed acute toxicity as well as death of most of the experimented animals (Minton 2003). These drastic outcomes shifted to the use of a nonpathogenic strain of Clostridium, which showed its potentiality to colonize anaerobic parts of the tumor after intravenous administration, but the outcome was not satisfactory in terms of tumor regression (Carey et al. 1967). Anaerobic bacterial species such as Clostridium novyi demonstrated significant antitumor activity but showed lethal effects on experimental animals. The attenuated C. novyi-NT exhibited significant antitumor effects but also showed severe toxicity. The use of obligate anaerobic bacteria or facultative anaerobic as alternative cancer therapeutics has been followed over more than a century due to the insights gained over time on host–bacteria interactions, genome information for many of the bacteria employed, and especially efficient molecular tools. A number of bacterial species have proven their tumor therapeutic effects in murine model systems. The lack of effectiveness of these bacterial therapies encouraged continuous efforts to identify other novel bacterial strains as anticancer therapeutic tools.
Infections in a Modern Society
Published in Keith Struthers, Clinical Microbiology, 2017
It is likely that injected drugs contain particulate impurities which, travelling at speed, impinge on and damage the endothelium of the tricuspid valve. The resulting deposition of fibrin and platelets at this site is ideal for bacteria in the blood to settle in and initiate endocarditis. Microbial contamination of drugs can also be a major issue. Clostridium novyi is one example and it can cause fulminating systemic infection.
Synthetic engineered bacteria for cancer therapy
Published in Expert Opinion on Drug Delivery, 2023
Nevertheless, many crucial issues for bacteriotherapy in cancer need to be considered. One of the most important problems is the safety concern. Live bacterial products as well as coated cargo may have the potential to induce infection or sepsis after being administered into the host. One way to solve this problem is to delete certain genes to reduce their pathogenicity. For example, Dang, L. H. et al. transformed a Clostridium novyi strain into a much safer strain (C. novyi NT) by deleting an exotoxin-coding gene [56]. Similarly, a Salmonella sp. strain was much less toxic when the gene msbB, which is responsible for lipid A (a component of LPS), was deleted [176]. Another method is to allow bacteria to grow only around cancer. For example, Salmonella A1-R was engineered into an auxotrophic mutant strain that only grew in a leucine and arginine-enriched environment, such as a tumor [177]. Likewise, EcN was engineered to bind specifically to the heparan sulfate proteoglycan on colorectal cancer cells and was detached from the colorectal tissue after the tumor was cleared [155]. All these methods have largely improved the bacteriotherapy safety.
Trial watch: intratumoral immunotherapy
Published in OncoImmunology, 2021
Juliette Humeau, Julie Le Naour, Lorenzo Galluzzi, Guido Kroemer, Jonathan G. Pol
Since the early approval of BCG in bladder cancer, additional weakened strains of bacteria are applying to join the armamentarium of cancer treatments. By stimulating multiple PRRs, such as TLR2 and TLR4, and by providing xenoantigens, bacteria attract and activate immune sentinels, and can stimulate antitumor immune activity with reduced toxicity.183–185 In particular, anaerobic strains, which preferentially replicate within tumors, are the objects of several clinical trials. For instance, Clostridium novyi-NT186–188 is being tested i.t. in combination with i.v. pembrolizumab and oral doxycycline in subjects with advanced solid malignancies (NCT03435952) (Table 2). While patient enrollment continues, intermediary results from nine patients demonstrated encouraging signals of antineoplastic activity and a manageable toxicity profile.189
Bioengineered smart bacterial carriers for combinational targeted therapy of solid tumours
Published in Journal of Drug Targeting, 2020
Siamak Alizadeh, Abolghasem Esmaeili, Abolfazl Barzegari, Mohammad A. Rafi, Yadollah Omidi
The hypoxic response is mediated with the binding of hypoxia-inducible factors (HIFs) to the regulatory elements in the promoter regions of target genes, so-called hypoxia-response elements (HREs) [71]. Since the HRE/HIF-1 regulation system is deregulated in 70% of cancers, its targeting could be an interesting strategy for cancer treatment [72]. Tumour hypoxia can be targeted by different approaches, including hypoxia-activated prodrugs/linkers inhibitors, hypoxia-inducible factor 1 alpha (HIF-1α) inhibitors and obligatory anaerobic bacteria-mediated targeting method [64]. Bacteria can actively penetrate tumour tissue, in which they can simply be detected and controllably induce toxicity. Several facultative or obligate anaerobic bacteria (especially Clostridium species such as C. histolyticium, C. tetani, and C. oncolyticum) have been shown to selectively target and directly/indirectly deliver therapeutic agents to hypoxic and necrotic regions of solid tumours [73]. An obligatory anaerobic bacterium is suitable for targeting large primary tumours because the hypoxic region is present in tumours but not in healthy cells. Facultative anaerobes, however, are appropriate for targeting metastases and outside regions of tumour necrosis since their attraction to tumour site relies on chemotaxis [38,74]. In a study, genetically modified Clostridium novyi-NT were successfully used in combination with radiation and chemotherapies and resulted in the increased efficacy of therapy [75]. Therefore, the hypoxia-inducible elements have been designed for the expression of anticancer agents or genetic materials with major safety concerns in anaerobic bacteria (Figure 3(A)) [76,77].