Talk:Clostridium novyi

I've added the following brief section on clostridium novyi-NT and it's uses as a cancer treatment. Obviously this is a rapidly evolving area so please expand/extend it as new work comes in. Please also feel free to clean up &/or extend the reference section if you have time...

I don't know if someone wants to create a separate page for clostridium novyi-NT at this point. It seems to make sense to me to keep it on the same page, but I leave this with you.

Thank you.

             (Gerhard Holt  ghol7955@gmp.usyd.edu.au)

Clostridium novyi-NT - Potential Therapeutic Uses in Cancers

Solid tumors are generally characterized by a hypoxic area in the tumor cores. This is generally due to irregular and insufficient tumor vasculature growth and heavy metabolic demands of the surrounding tumor cells.

Much of a tumor core is necrotic, however some tumor cells survive there - often in a quiescent state. These cells are often therefore quite resistant to standard treatments such as radiotherapy (which relies heavily on DNA damage from radiation induction of oxygen based free radical species), and chemotherapy (which (1) can have difficulty accessing the poorly perfused tumor core, and (2) often has weak effect on quiescent cells.). As a result, cells in the hypoxic tumor core often survive treatment and become a source for subsequent cancer recurrence and spread.

Clostridium novyi-NT is a genetically modified form of Clostridium novyi which lacks a major toxin. Because Clostridium novyi is a strict anaerobe, it grows selectively in hypoxic tumor cores, elsewhere it forms inactive spores. Clostridium novyi-NT activates and very effectively infects and lyses tumor cells in hypoxic tumor cores.

Early work on use of strict anaerobes in tumors goes back several decades. Strongly lytic, infective bacteria tended to be the most effective (however most earlier research was abandoned due to the risk of toxicity from release of toxin).

One major limitation on the use of Clostridium novyi-NT or other strict anaerobes in cancer treatment - is that it tends ONLY to effect the hypoxic tumor core - leaving the active cancer cells in the well perfused tumor rim alive and intact.

Not surprisingly, this has lead to attempts to combine Clostridium novyi-NT with traditional chemotherapy and/or with radiotherapy (both of which tend to be preferentially effective within the well-perfused tumor rim).

A variety of other clever approaches are under continuing investigation, these include :

1) "RAIT" (radioactive immunotherapy) - Radioactive monoclonal antibodies against common antigens on the tumor cells (for example CEA) - or perhaps against epitopes on the Clostridium novyi-NT itself) can be used to more specifically localize and deliver radiation near the tumor cells and less to surrounding tissue. (In a sense this could be viewed as a sort of molecular brachytherapy).

2) Prodrug converting enzymes can be produced by further genetic modification of the Clostridium novyi-NT. Chemotheraputic prodrugs can be given systemically and then will be more specifically activated near the tumor site.

3) Other chemotherapy delivery technologies using liposomes or minicells can be used to more specifically deliver chemotheraputic agents to the site of the remaining tumor rim. (Again, it may be useful to use bispecific antibodies to epitopes on the Clostridium novyi-NT itself - instead of just using bispecific antibodies to variably expressed tumor antigens (like CEA). (Minicells are a very promising technology in themselves that uses bispecific antibodies to dramatically increase the delivery specificity of chemotheraputic drugs by several orders of magnitude - potentially allowing effective chemotheraputic dosages that are 100s of times current tolerated systemic levels. (Nevertheless minicells are limited by perfusion access to tumor cores - so combination with Clostridium novyi-NT may provide an excellent complement).

4) Various genetic modifications to Clostridium novyi-NT seek to further stimulate local inflammation and immune response - to boost the immunogenicity of the tumor rim. Many of these approaches secrete immunomodulators / cytokines, others try to use siRNA or other approaches to further shut down tumor cells.

5) The hypoxic core can be made temporarily wider by use of drugs like dolastatin, or by temporarily reducing oxygenation. This then allows Clostridium novyi-NT to lyse more of the tumor.

6) Most approaches have used single administrations of Clostridium novyi-NT, but it may be useful to give repeated injections to promote immune response in the area of the active bacteria (the former tumor core and adjacent rim) to create a "bystander effect" on the nearby tumor cells (eg. boosting the immune response not only to the Clostridium novyi-NT, but to the tumor cells). It may also help slow relapses by colonizing metastases early (although only after they became large enough to have a significantly sized hypoxic core).

In summary, Clostridium novyi-NT is a promising new component to treatment of solid tumors - effectively targeting the hypoxic tumor cores that were a source of ongoing treatment resistance and recurrence. It is likely that additional modalities will be needed to treat the well perfused tumor rims.

References

Gottschalk G. "Clostridia : molecular biology in the post genomic era". 2008. Chapter 11 : "Clostridia in Anti-tumour therapy" by Mengesha et al.

Bettegowda C et al. "Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria". Dec 9, 2003. PNAS.

Groot AJ et al. "Functional antibodies produced by oncolytic clostridia" 2007. Biochem Biophysics Research Communication. (PMID 17971292)

Dang et al. "Combination bacteriolytic therapy for the treatment of experimental tumors" Dec 18, 2001. PNAS.

Jean et al. "Bacterial therapies : completing the cancer treatment toolbox" Current Opinion in Biotechnology. 2008.

Removing original research

A review of the literature reveals that the organism Clostridium novyi type A is capable of inducing most of the symptoms of type 2 diabetes and its complications. There is also anecdotal evidence that claim that antibiotic treatment for this organism produces remission of these symptoms.[21]

This claim is original research by Andy Bidduph: http://en.wikipedia.org/w/index.php?title=Clostridium_novyi&diff=398630550&oldid=373816258 The source referenced is his own, now non-existent Knol account. See also: User_talk:Andybiddulph Special:Contributions/Andybiddulph 91.77.66.232 (talk) 23:39, 14 October 2012 (UTC)

Notably strange single case?

The Lancet reported the bizarre case of a man who suffered from an inexplicably persistent Clostridium infection. It caused a terrible odor but no other ill effects and it disappeared just as mysteriously after five years. Might this be noteworthy?

"A skin biopsy sample was normal but culture of the sample yielded a Clostridium novyi type B-like organism which could not be eradicated by prolonged courses of antibiotic therapy (despite exquisite sensitivities in vitro) or by hyperbaric oxygen treatment (RAF Hospital Wroughton) over a 2-month period."

References