Effect of Histolyticus Infection and Toxin on Transplantable Mouse Tumors.

Parker, Raymond C.; Plummer, Helen; Siebenmann, Charles O.; Chapman, Marion G.

doi:10.3181/00379727-66-16124

Cited by 91 publications

(65 citation statements)

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“…What is less well recognized is that this neoangiogenesis often does not keep pace with the growth of the neoplastic cells, resulting in large necrotic areas composed of dead or dying cells. For example, we found that each of 20 randomly selected liver metastases Ͼ1 cm 3 in size contained relatively large avascular regions, in general constituting 25-75% of the tumor mass ( Fig. 1).…”

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confidence: 97%

“…We chose to investigate anaerobic bacteria for this purpose. It has been recognized for half a century that such bacteria could selectively proliferate in the hypoxic regions of tumors (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Clever strategies for potentially exploiting such bacteria for diagnostic and therapeutic purposes have been devised, although relatively little work in this area has recently taken place.…”

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confidence: 99%

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Combination bacteriolytic therapy for the treatment of experimental tumors

Dang

Bettegowda

Huso

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

501

488

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Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising. We created a strain of C. novyi devoid of its lethal toxin (C. novyi-NT) and showed that intravenously injected C. novyi-NT spores germinated within the avascular regions of tumors in mice and destroyed surrounding viable tumor cells. When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 h, resulting in significant and prolonged antitumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a new dimension to the treatment of cancer.

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confidence: 97%

mentioning

confidence: 99%

Combination bacteriolytic therapy for the treatment of experimental tumors

Dang

Bettegowda

Huso

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

501

488

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“…Motile, nonpathogenic bacteria have the potential to overcome multidrug resistance (1) because they can penetrate deeper than passively diffusing drug molecules (2)(3)(4)(5). Multidrug resistance, which significantly reduces the effectiveness of most cancer therapeutics, is caused by two mechanisms: limited drug penetration and poor cell susceptibility (6,7).…”

Section: Introductionmentioning

confidence: 99%

Salmonella typhimurium Lacking Ribose Chemoreceptors Localize in Tumor Quiescence and Induce Apoptosis

Kasinskas¹,

2007

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The effectiveness of most chemotherapeutics is limited by their inability to penetrate deep into tumor tissue and their ineffectiveness against quiescent cells. Motile Salmonella typhimurium, which are specifically attracted to compounds produced by quiescent cancer cells, could overcome this therapeutic barrier. We hypothesized that individual chemoreceptors target S. typhimurium to specific tumor microenvironments. To test this hypothesis, we used time-lapse fluorescent microscopy and tumor cylindroids to quantify the accumulation of chemotaxis machinery knockouts, including strains lacking individual cell surface chemoreceptors, chemotaxis signal transduction pathway enzymes, and the flagella and motor assemblies. To measure the extent of apoptosis induced by individual bacterial strains, caspase-3 activity was measured as a function of time. Our results showed how chemoreceptors directed bacterial chemotaxis within cylindroids: the aspartate receptor initiated chemotaxis toward cylindroids, the serine receptor initiated penetration, and the ribose/galactose receptor directed S. typhimurium toward necrosis. In addition, strains lacking proper flagella constructs, signal transduction proteins, or active motor function did not chemotax toward tumor cylindroids, indicating that directed chemotaxis is necessary to promote accumulation in tumors. By deleting the ribose/galactose receptor, bacterial accumulation localized to tumor quiescence and had a greater individual effect on inducing apoptosis than wild-type S. typhimurium. This new understanding of the mechanisms of Salmonella migration in tumors will allow for the development of bacterial therapies with improved targeting to therapeutically inaccessible regions of tumors. [Cancer Res 2007;67(7):3201-9]

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“…7 In 1947, it was shown that the injection of spores of Clostridium histolyticus caused oncolysis, then referred to as "liquefaction," of a transplanted mouse sarcoma. 8 Clostridium tetani spores were also used and tumor-bearing mice died 48 hours after the treatment in contrast to the healthy controls. 9 This experience proved that a specific microenvironment is required to bacterial survival and development but also that toxicity remained a problem with live bacteria.…”

Section: Live Attenuated and Engineered Bacterial Strains In The Trementioning

confidence: 99%