The
hypothesis that living bacteria may function as anticancer therapeutic agents
was first advanced in the middle of the twentieth century. Due to the obstacles
of hypoxia and necrosis, accessing tumor tissue with traditional treatments has
proved difficult. However, bacteria may actively migrate away from the
vasculature and penetrate deep into tumor tissue and accumulate (Fig. 1A).
Three classes of anaerobic and facultative anaerobes have been examined for use
inanticancer therapy (1,2): Bifidobacteria, facultative intracellular bacteria
and strictly anaerobic bacteria. The ideal criteria for the selection of
therapeutic bacteria (3,4) are as follows: Non-toxic to the host; selective for
a specific type of tumor; has the ability to penetrate deeply into the tumor
where ordinary treatment does not reach; non-immunogenic (does not trigger an
immune response immediately but may be cleared by the host); harmless to normal
tissue; able to be manipulated easily; and has a drug carrier that may be
controlled. In addition to studies of bacteria designed to induce immune
responses (5)and mediate antiangiogenesis therapy (6), a recent study has
focused on the usage of bacterial products as anticancer agents (7). Three main
strategies in bacterial cancer treatment are discussed : i) Bacteria as tumor
markers; ii) Bacteria engineered to express anticancer agents (Fig. 1B); and
iii) Bacteria for oncolytic therapy (Fig. 1C).
Bacteria as tumor markers
As
replicating anaerobic bacteria are able to selectively target tumors, the use
of these bacteria may be an innovative approach for locating tumors that is
simple and direct, but practical and effective. Two types of non-bacterial
material have served as tumor markers: Viral vectors, including adenovirus,
adeno-associated virus, herpes simplex virus (HSV)-1, HSV amplicon, Sindbis,
poliovirus replicon and lentivirus/Moloney murine leukemia virus; and non-viral
vectors, such as therapeutic DNA, microRNA, short
hairpin (sh)RNA, small interfering (si)RNA and oligodeoxynucleotides (ODNs) (14-16).
However, anaerobic bacteria are preferable to these other two types of tumor
marker due to increased mobility. Once the marker has been administered, a
number of methods may be used to locate the tumor, including bioluminescence,
fluorescence and magnetic resonance imaging (MRI), as well as positron emission
tomography (17). Bacteria may be detected using light, MRI or positron emission
tomography (18,19).
Bacteria engineered to express anticancer agents
Bacteria exhibit the ability to manufacture and deliver
specific materials; these can be artificially coupled to certain anticancer
agents (Fig. 1B) (18). The most common current carriers employed ingene therapy
are viral vectors, such as retrovirus, adenovirus, viral vaccines, herpes
simplex virus and adeno-associated virus. Non-viral delivery systems have been
gradually established with the development of technology; currently, the gene
therapy field has evolved to encompass not only the delivery of therapeutic
DNA, but also of microRNA, shRNA, siRNA and ODNs (4). However, non-viral gene
delivery systems exhibit lower transfection potency, resulting in lowered
ability to traverse the various obstacles encountered during treatment.
Conversely, bacteria have great advantages in the drug carrier field. Two
predominant mechanisms have
been investigated: The direct expression of antitumor proteins and the transfer
of eukaryotic expression vectors into infected cancer cells. In direct
expression, four categories of anticancer therapies may be utilized: Proteins
with physiological activity against tumors, cytotoxic agents, antiangiogenic
agents or enzymes that convert the nonfunctional prodrug to an anticancer drug.
In the transfer of eukaryotic expression vectors, gene-silencing shRNAs (20),
cytokines and growth factors, and tumor antigens have been investigated (21).
Furthermore, the number of useful
agents is increasing due to new developments in combinatorial synthesis and the
advent of metagenomics, which is an unlimited source of novel anticancer
bacterial products. Bacterial oncolytic therapy. The employment of
bacteria in oncolytic therapy is the initial treatment and most direct method
to kill tumor cells. Clostridial spores are the main components in oncolytic
therapy and have been thoroughly analyzed (6,22,23). Bacterial-based cancer
therapies usingClostridium spores have the advantage of overcoming the
obstacles of hypoxia and necrosis (24). Clostridium spp. are strictly anaerobic
and only colonize areas devoid of oxygen; therefore, when Clostridium spp. are
systematically injected into solid tumors, spores germinate and multiply in the
hypoxic/necrotic regions. Parker et al were the first to demonstrate clostridial
oncolysis and tumor regression in mouse tumors by injecting a Clostridium spore
suspension into transplanted mouse sarcomas 25). However, during follow-up
studies, spore treatment with wild-type Clostridium was not sufficient to
eradicate solid tumors (2,8,9). Thus, genetic engineering and repetitive
screens are required to enhance the tumor oncolytic capacity of Clostridium.
M-55, which was isolated from a non-pathogenic Clostridium oncolyticum strain
by Carey et al (10,11), broke this impasse. Since then, multitudinous
recombinant Clostridium strains have been used in tumor treatment. Among these,
C. histolyticium, C. tetani, C. oncolyticum, C. oncolyticum (sporogenes), C.
beijer‑ inckii (acetobutylicum) and C. novyi‑NT have been the most commonly
investigated (12,13).
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***Adapted
from:LIU et al: TUMOR-TARGETING BACTERIAL THERAPY IN TREATMENT OF ORAL
CANCERONCOLOGY LETTERS 8: 2359-2366, 2014
Macherki M E
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