Research
Good Bacteria
Part 1
New Bacteria Target Cancers In Mice
 12-5-2001
Scientists from the Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins have created bacteria that selectively
target large advanced tumors in mice. Results of their
experiments are reported in the November 27, 2001 issue
of the Proceedings of the National Academy of Sciences.
The
scientists found a way to exploit a special germ’s
taste for oxygen-starved environments and direct them
to target pockets of dead and dying cells within large
tumors. These advanced tumors generally have areas of
poor blood circulation and thus little oxygen. The lack
of oxygen renders them relatively resistant to conventional
chemotherapy and radiation but open to bacteria that
can grow without oxygen.
"The
idea is to selectively attack these tumors from inside
with the bacteria and from the outside with chemotherapy,"
says Bert Vogelstein, M.D., Clayton Professor of Oncology
and Investigator, Howard Hughes Medical Institute.
The
scientists systematically screened numerous bacterial
species to find one that would thrive in an oxygen-poor
environment and, at the same time, destroy surrounding
tumor cells. They settled on one spore-forming bacterial
species, called Clostridium novyi (C.novyi).
C.novyi is normally found in soil and dust
and contains a toxin that can cause lethal side effects
in animals. They genetically modified the bacteria to
remove the toxin gene to make them harmless to normal
animals. Then, they injected spores of these bacteria
and conventional chemotherapeutic agents into mice with
large tumors composed of transplanted human colon cancer
cells.
The
results achieved with this strategy, called COBALT for
combination bacteriolytic therapy were dramatic. More
than half of the tumors treated, including very large
tumors, were completely destroyed within 24 hours. The
tumors decomposed and turned into blackened scars, while
the surrounding healthy tissues remained intact. The
tumor scars then gradually disappeared over the next
two weeks, leaving healthy tissue behind.
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Clinical
trials are not planned at this time as it will take several years
to determine which chemotherapy agents make the best combinations
and to develop strategies to avoid the toxicity associated with rapid
destruction of large tumor masses. "We hope that this research
will add a new dimension to cancer treatment, but realize that the
way tumors respond to treatment in mice can be different than in humans,"
says Kenneth Kinzler, Ph.D., professor of oncology.
Funding
for this research was provided by the Miracle Foundation, the National
Colorectal Cancer Research Alliance, the Clayton Fund, and the National
Institutes of Health.
In addition
to Vogelstein and Kinzler, participants of this research include Long
H. Dang, Chetan Bettegowda, and David L. Huso from the Sidney Kimmel
Comprehensive Cancer Center at Johns Hopkins.
This
story has been adapted from a news release issued by Johns Hopkins
Medical Institutions, www.hopkinsmedicine.org.
Follow-Up
I am
so curious and excited about the potential for these helpful bacteria
as a cure for cancer that I want to report some further research that
has been done. (This is sorted in descending date order.)
"Bacteriolytic
therapy can generate a potent immune response against experimental
tumors."
AUTHORS:
Agrawal N, Bettegowda C, Cheong I, Geschwind JF, Drake CG, Hipkiss
EL, Tatsumi M, Dang LH, Diaz LA Jr, Pomper M, Abusedera M, Wahl
RL, Kinzler KW, Zhou S, Huso DL, Vogelstein B.
Howard
Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore,
MD 21231, USA.
ABSTRACT:
"When spores of the anaerobic bacterium Clostridium novyi-NT
are systemically injected into animals, they germinate exclusively
within the hypoxic regions of cancers. The germinated bacteria destroy
adjacent tumor cells but spare a rim of well oxygenated tumor cells
that subsequently expand. Surprisingly, we found that approximately
30% of mice treated with such spores were cured of their cancers
despite the viable tumor rim initially remaining after spore germination.
The mechanism underlying this effect was shown to be immune-mediated,
because cured animals rejected a subsequent challenge of the same
tumor. Similar effects were observed in rabbits with intrahepatic
tumors. It was particularly notable that the induced immune response,
when combined with the bacteriolytic effects of C. novyi-NT,
could eradicate large established tumors."
REFERENCE:
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15172-7. Epub 2004
Oct 7
"Targeting
vascular and avascular compartments of tumors with C. novyi-NT
and anti-microtubule agents"
AUTHORS:
Dang LH, Bettegowda C, Agrawal N, Cheong I, Huso D, Frost P, Loganzo
F, Greenberger L, Barkoczy J, Pettit GR, Smith AB 3rd, Gurulingappa
H, Khan S, Parmigiani G, Kinzler KW, Zhou S, Vogelstein B.
Howard Hughes Medical Institute and Sidney Kimmel
Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland,
USA.
ABSTRACT:
"Current approaches for treating cancer are limited, in part,
by the inability of drugs to affect the poorly vascularized regions
of tumors. We have found that C. novyi-NT in combination
with anti-microtubule agents can cause the destruction of both the
vascular and avascular compartments of tumors. The two classes of
microtubule inhibitors were found to exert markedly different effects.
Some agents that inhibited microtubule synthesis, such as HTI-286
and vinorelbine, caused rapid, massive hemorrhagic necrosis when
used in combination with C. novyi-NT. In contrast, agents
that stabilized microtubules, such as the taxanes docetaxel and
MAC-321, resulted in slow tumor regressions that killed most neoplastic
cells. Remaining cells in the poorly perfused regions of tumors
could be eradicated by C. novyi-NT. Mechanistic studies
showed that the microtubule destabilizers, but not the microtubule
stabilizers, radically reduced blood flow to tumors, thereby enlarging
the hypoxic niche in which C. novyi-NT spores could germinate.
A single intravenous injection of C. novyi-NT plus selected
anti-microtubule agents was able to cause regressions of several
human tumor xenografts in nude mice in the absence of excessive
toxicity."
REFERENCE:
Cancer Biol Ther. 2004 Mar;3(3):326-37. Epub 2004 Mar 12
"Overcoming the hypoxic barrier
to radiation therapy with anaerobic bacteria"
AUTHORS:
Bettegowda C, Dang LH, Abrams R, Huso DL, Dillehay L, Cheong I, Agrawal
N, Borzillary S, McCaffery JM, Watson EL, Lin KS, Bunz F, Baidoo K,
Pomper MG, Kinzler KW, Vogelstein B, Zhou S.
Howard Hughes
Medical Institute and Sidney Kimmel Cancer Center, Johns Hopkins
Medical Institutions, Baltimore, MD 21231, USA.
ABSTRACT: "The
low level of oxygenation within tumors is a major cause of radiation
treatment failures. We theorized that anaerobic bacteria that can
selectively destroy the hypoxic regions of tumors would enhance
the effects of radiation. To test this hypothesis, we used spores
of Clostridium novyi-NT to treat transplanted tumors in
mice. The bacteria were found to markedly improve the efficacy of
radiotherapy in several of the mouse models tested. Enhancement
was noted with external beam radiation derived from a Cs-137 source,
systemic radioimmunotherapy with an I-131-conjugated monoclonal
antibody, and a previously undescribed form of experimental brachytherapy
using plaques loaded with I-125 seeds. C. novyi-NT spores
added little toxicity to the radiotherapeutic regimens, and the
combination resulted in long-term remissions in a significant fraction
of animals."
REFERENCE: Proc
Natl Acad Sci U S A. 2003 Dec 9;100(25):15083-8. Epub 2003 Dec 1
"Combination
bacteriolytic therapy for the treatment of experimental tumors"
AUTHORS:
Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B.
The Howard Hughes
Medical Institute, Program in Cellular and Molecular Medicine, The
Johns Hopkins School of Medicine, and The Johns Hopkins Oncology
Center, Baltimore, MD 21231, USA.
ABSTRACT:
"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."
REFERENCE: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15155-60.
Epub 2001 Nov 27
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