Download Role of clostridium spores in cancer treatment

ROLE OF CLOSTRIDIUM SPORES IN
CANCER TREATMENT
AND THEIR POTENTIAL AS DRUG
DELIVERY SYSTEM
CONTENT
Introduction
 History
 What we mean by Spores
 What we mean by Cancer
 Mechanism of clostridia anticancer effect
 Examples
 Types of spores used
 Cancer types treated

INTRODUCTION
Microorganisms are beneficial in
 Decomposition
 Food industry
 Medicine industry : antibiotics, vaccines
 Cancer treatment!!!

HISTORY

Patients diagnosed with cancer reported
unexpected cure of illness after gangrene
infection caused by Clostridium perfringens.
Later experiments investigated clostridia role in
treating cancer
SPORES
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Spores are dormant structure of vegetative cell either
bacterial or fungal. When they are bacterial in origin we
call them endospores (simply spores)and when they are
fungal in origin we call them exospores
Endospores are formed when certain cells species that are
gram positive bacteria like Bacillus and Clostridium spp.
encounter environmental stresses like nutrient starvation
Endospores have evolved many mechanisms to protect
themselves from damage withstand harsh conditions and
survive many years or even millions of years in that
dormant state
SPORE GERMINATION
When shock occurs and favorable environment
dominates the bacteria regenerate
 those steps called activation, germination and
outgrowth

CANCER


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It is a class of disease characterized by uncontrolled cell
division, leading to abnormal growth. In tumor (cancerous)
cells we lose the balance between signals enhancing and
suppressing growth.
The predisposing factor may be genetic, environmental ,
chemical exposure or harmful conditions like radiations
which alter the genomic structure and processes
There are different ways to treat cancer including
radiotherapy, chemotherapy, and immunotherapy, surgery,
hormone therapy and microorganisms
CANCER EPIDEMIOLOGY

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In 2012 there were 14 million new cancer cases occurring
worldwide, which contributed to around 8.2 million deaths.
It is predicted that within the next 15 years the burden of
cancer will increase to 23.6 million.
Those statistics shows that cancer is still one of the leading
causes of death worldwide so we need more effective and
reachable treatments
MECHANISM BEHIND CLOSTRIDIUM
ANTICANCER EFFECT
Clostridium spp. as such has anticancer effect
 Clostridium spp. act as drug delivery system ↔
CDEPT (Clostridia directed enzyme prodrug
therapy)
 In either ways our targeting mechanism is tumor
hypoxia
 What is tumor hypoxia?

WHAT IS HYPOXIA
WHY ARE WE INTERESTED IN TUMOR
HYPOXIA?

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80% of cancerous tumors are solid tumors. Most solid
tumors cores are poorly oxygenated tissue “hypoxic tumor”
necrotic core
Tumor hypoxia reduce the effect of many anti-cancer drugs
due to poor drug penetration related to poor
vascularization , it also activates metastasis
Patients diagnosed and surgically treated for primary
tumors with severe hypoxia have lower survival
As we see hypoxic tumor treatment is challenging and we
need novel therapies
NOVEL STRATEGIES OF HYPOXIC TUMOR
THERAPY:

DEPT (directed enzyme prodrug therapy): hypoxia
activates spores that germinate to bacteria and activate a prodrug
into drug
DEPT includes :
 a-ADEPT (anti-body directed prodrug therapy): Fusion of

PCE to a tumor specific antibody

b- GDEPT (gene-Directed Enzyme prodrug therapy):
delivery of gene encoding PCE using viral or non-viral vectors

C-CDEPT (Clostridia directed enzyme prodrug therapy):
CDEPT
CDEPT (Clostridia directed enzyme prodrug therapy):

Anaerobic spore producing bacteria are modified
genetically to produce PCE (prodrug converting enzyme).
Then modified spores are produced to act as delivery
system. Spores are injected. Once in necrotic tissue they
will exclusively germinate and colonize to target tissue and
start to produce PCE that converts the safe prodrug in the
vicinity to very toxic drug with anticancer effect acting
locally.
COMBINATION THERAPY WITH SPORES (CLOSTRIDIA DIRECTED
ENZYME PRODRUG THERAPY CDEPT):
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The use of Clostridium strains was of great benefit, but
later on it was discovered that combining it with noxia was
more promising.
One of the noxia choices was prodrug-drug stragety
Ideal cancer therapy should be selective on tumor tissue
this can be achieved targeting a safe prodrug that is
converted into highly toxic drug only in tumor tissue using
prodrug converting enzyme PCE  this procedure is called
Directed Enzyme Prodrug Therapy (DEPT)
(DEPT) can assure selective exposure of cells to effective
dose .
EXAMPLES OF EFFECTIVE COMBINATIONS
1- novel PR-104 : alkylating agent ( DNA
cross-linking agent), bioreductive
dinitrobenzamide mustard
2-5-fluorocytosie (5-FC) converted to5fluorouracil (5-FU) :
CPE :Cytosine deaminase(codA) , 500-fold enhancement of
cytotoxicity towards murine tumourcells, the used species
was :C. beijerinckii NCIMB 8052
WHAT TYPE OF SPORES CAN BE USED ?
to satisfy that mechanism of action behind
this theory
 1-anaerobic
 2- non-pathogenic spores must be used

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The non-pathogenic species is the ones of importance in our
delivery system like:
1- Proteolytic Species was of superior efficacy due to
tumor destruction eg:
a –Clostridium butyricum M-55 which showed significant
oncolytic effects the strain was named Clostridium oncolyticum
and later reclassified as Clostridium sporogenes M-55

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b- Clostridium novyi-NT
2- Saccharolytic Clostridia such as Clostridium
beijerinckii or Clostridium acetobutylicum which was effective but
inferior to C. sporogenes
WHAT TYPE OF CANCER CAN BE TARGETED ?

Solid tumors as associated with hypoxia like
refractory/relapsed acute leukemia
RESISTANCE

This method is still under investigation and
nothing about resistance is studied
CONCLUSION
1- Clostridium genotype is altered to express the
required PCE , all used genotypes carry plasmid
responsible for antiabiotic resistance .
2-Clostridial-Directed Enzyme Prodrug Therapy
CDEPT strain used to achieve substantial
tumour suppression, and in some cases cure.
3-clostridia species seem destined to have a
significant role to play in the future treatment of
solid tumours.