Bacteria for cancer treatment
The article by James Byrne Bacteria, the anti-cancer soldier is published in the Scientific American Blogging Network.
Translated by Evgenia Ryabtseva
Everyone knows what cancer is. According to WHO statistics, eight million people died from various types of cancer in 2007. According to experts, by 2030 this figure will increase to 12 million.
Unlike many other significant diseases, the incidence of cancer is not associated with factors such as living on a particular continent or belonging to a particular socio-economic group. In addition, unlike other representatives of the WHO's "hot ten", there is no vaccine or effective medicine against cancer. Treatment of this insidious disease requires surgery and chemotherapy or radiotherapy. All these procedures have a detrimental effect on the patient's health both during their implementation and, often, for a long period after the end of treatment.
However, recent research results indicate that the use of certain bacteria for the treatment of cancer may provide new therapeutic approaches that are both cheap, easy to implement and, if the preliminary results obtained so far are confirmed in further studies, capable of providing complete remission in some cases.
The new is the well–forgotten old. Back in the early 19th century, researchers, including Vautier, noted that before death from the underlying disease, patients with gangrene had a complete disappearance of tumors, but the gangrene-causing agent was not known at that time. From time to time, cases of self-healing of tumors in patients with gangrene and acute superficial cellulite (erysipelas) have been described in the medical literature and very informative observations have been made.
For example, Dr. William Coley (1920) writes: "In my practice, there was one case of malignant round-cell sarcoma of the neck. During the operation to remove the tumor, it was found that it had affected the deeper tissues of the neck, on the basis of which attempts to remove the tumor were not made. The patient had two episodes of erysipelas. During these episodes, the neck tumor completely disappeared and the patient left the clinic in good health. I was interested in his future fate, and after 7 years I found him alive and well." But several more decades passed before the first attempts to study this phenomenon on animals.
The expediency of using bacteria is limited to certain types of cancer, since a necessary requirement for the effectiveness of this therapy is the large size of the tumor, which causes the death of cells of its inner nucleus. As the cancer cells grow, they must constantly defeat the surrounding cells in the struggle for resources. To do this, they use mutations to disable various mechanisms for controlling cell growth, such as checking the good state of DNA before dividing, or begin to secrete factors that stimulate their own growth. The end result of this is the formation of a tumor mass.
Over time, this becomes a problem for the tumor, since nutrients and, especially, oxygen can penetrate into the tissues only up to the level of capillaries. If the thickness of the tissue layer between the capillaries becomes too large, cell death occurs in areas where nutrients cannot penetrate.
This limits the growth of the tumor, since there are malignant cells among the dying cells. The universal solution to this problem is angiogenesis – the formation of new blood vessels, which requires the presence of angiogenic signals and cells in a state of hypoxia to start. The ability of malignant cells to stimulate angiogenesis is inherent in almost all tumors whose diameter exceeds 1 mm, or located at a distance of 100 mm from the nearest blood vessel.
Most tumors begin to grow in the thickness of healthy tissues. The latent phase (a) continues as long as they have enough incoming nutrients. When the resources of the local environment are exhausted, their death begins in parallel with the rapid division of malignant cells. Cell death, mainly due to hypoxia, triggers angiogenesis, restoring the influx of nutrients and stimulating further tumor growth. Angiogenesis begins with the dissection of the wall of an existing vessel and its expansion (b), after which an angiogenic germ appears (c), the formation and maturation of a new vessel and its settlement with perivascular cells (d). Angiogenesis continues throughout the process of tumor growth, while new blood vessels selectively supply oxygen-depleted and necrotic areas of the tumor essential nutrients and oxygen (e). Figure from the article Bergers, G. & Benjamin, L. E. (2003). Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3, 401-410.
The newly formed nutrient delivery system allows the tumor to continue growing, but its size increases rapidly and its central part sooner or later goes beyond the zone supplied with nutrients, after which the cells of the central part of such tumors are doomed to death.
Large tumors with dead or necrotic centers (necrosis zones can be represented by either one large nucleus or numerous small foci in the center of the tumor tissue) are very common. In many cases, in the presence of metastases, the presence of a necrotic center is a sign of a primary tumor. This makes them a very interesting target for exposure to drugs, even though the ability of therapy directly aimed at suppressing necrosis to accelerate the recovery of patients has not been shown.
The existing limitations of traditional methods of antitumor therapy are quite well known and, for the most part, are due to the nature of these methods. The aim of chemo- and radiotherapy is to destroy all rapidly dividing cells, including malignant ones. However, there are other rapidly dividing cells in the body, so the side effects of such therapy are hair loss, weakening of the immune system, fatigue and infertility. The inability to target the therapy leads to serious tissue lesions associated with treatment. It is obvious that increasing the selectivity of chemo- and radiotherapy would significantly reduce their toxicity. However, how to act only on tumors?
That's where bacteria can come in handy. Certain types of bacteria – facultative anaerobes, such as Listeria monocytogenes and Salmonella, are able to grow and multiply in the absence of oxygen. In addition, there are also obligate anaerobes, including Clostridia (Clostridia), vital activity is possible only in anaerobic conditions.
Monocytogenic listeria was one of the most popular objects at the dawn of research on the possibility of using bacteria in the fight against cancer. This is due to the possibility, if necessary, to suppress with the help of antibiotics that part of the population of gram-positive microbes that is outside the tumor, in tissues with normal blood supply. This approach is very primitive, but in some cases provides regression of tumors. However, the specificity of this method remains questionable, since listeria not only did not "target" tumors directly, but preferred oxygen-supplied tissues to hypoxic tumor conditions, even in cases where recombinant listeria expressing tumor-specific antigens were used to increase the effectiveness of vaccination.
To increase the specificity of therapy, specialists turned their attention to anaerobic microorganisms capable of concentrating inside the necrotic center of the tumor. One of the most actively studied microorganisms was gram-negative facultative anaerobe salmonella. Despite the inherent ability of salmonella to infect any cells of the body, especially the cells lining the intestinal lumen, representatives of recombinant strains, devoid of amino acid synthesis mechanisms, preferred to multiply in necrotized tumor centers. Further modifications, such as blocking the mechanism of synthesis of lipid A (a component of a highly immunogenic polysaccharide), made bacteria even safer and reduced the likelihood of their spread throughout the body, retaining the ability to populate necrotic foci inside tumors.
However, the introduction of live viable cultures of an invasive pathogen to patients in any case is associated with a significant risk, so over time, scientists switched to looking for a safer alternative.
Returning to one of the earliest descriptions of the interaction between bacteria and tumors, the researchers drew attention to a microorganism with a number of properties that make it an ideal candidate for use in antitumor therapy, namely clostridium. Clostridium is an obligate anaerobe, whose vital activity and survival is possible only in an oxygen-deprived environment. This makes them an excellent weapon for targeting necrotic tissue, and also eliminates the possibility of developing a systemic disease caused by them.
Clostridia have another mechanism that should play into the hands of researchers. They are spore-forming bacteria, which ensures their metabolic activity exclusively in necrotic tissues and inertia in any other conditions. This is a significant advantage, since the introduction of inert spores that practically do not disturb the immune system is much safer than the introduction of viable invasive pathogens.
During the following years, studies did not bring great results, and only in the early 50s of the last century it was possible to eliminate tumors in experimental mice, but due to the lack of non-pathogenic strains, animals rarely experienced such treatment.
In the late 50s and early 60s, non-pathogenic strains of clostridium were identified, and in the mid–60s Mose and Mose made the next breakthrough. After the introduction of spores of a non–pathogenic strain of Clostridium butyricum contained in the environment (renamed Clostridium oncolyticum, and subsequently Clostridium sporogenes) directly into tumors, they demonstrated regression, and in some cases remission in experimental tumor models. According to their observations, after the introduction of spores, "the tumors became much softer and fluctuated during palpation," eventually they "broke through ... with the release of brownish liquid necrotic masses having the consistency of liquid pus."
These observations indicated that even non-pathogenic strains led to the death of some cells bordering on the necrotic centers of tumors. Later it was found that the death of these cells is due to the accumulation of toxic products of bacterial metabolism.
Despite the positive results obtained over the past 20 years, the use of bacteria as monotherapy for cancer treatment cannot be a solution to the problem. The real prospect lies in the use of combination therapy – the use of bacterial methods simultaneously with traditional approaches.
Many experts recognize the use of clostridium as the optimal approach to cancer therapy, but until recently, scientists had to rely only on natural strains of microorganisms and naturally occurring mutant forms. The emergence of genome manipulation methods was the beginning of a new stage in the development of bacterial cancer treatments.
Currently, the possibility of creating modified clostridium expressing enzymes that convert drug precursors into their active forms, including cytosine deaminase and thymidine kinase, is being actively studied. The first enzyme transforms non-toxic 5-fluorocytosine into cytotoxic 5–fluorouracil, and the second one phosphorylates ganciclovir, turning it into an active toxic agent. Precursor drugs can be administered in high concentrations, since their toxic forms will form exclusively in areas populated by bacteria expressing the corresponding enzymes.
Combination therapy has demonstrated significant potential, and currently numerous groups of researchers are working on bringing this method of antitumor therapy closer to clinical practice.
However, it is not yet known whether the methods of treating cancer with the help of anaerobic bacteria will justify the hopes placed on them. It is quite possible that the final stage of development may be combined approaches, in which chemotherapeutic agents will affect the tumor from the outside, and bacteria will kill it from the inside, and then sporulate under the influence of increased oxygen concentration.
Portal "Eternal youth" http://vechnayamolodost.ru11.03.2012