Factors that Influence Tissue Response to Radiation - Essay Example

www.academia-research.com Sumanta Sanyal d: 29/08/07 Factors that Influence Tissue Response to Radiation and Evidential Explanations for themIntroduction: Before beginning onto the body of the paper it is first necessary to define a few terms that are going to used throughout it. Firstly, in this sense, it becomes necessary to define what radiobiology is. The following puts it as aptly as is possible. Radiobiology is a branch of science that is concerned with the action of ionizing radiation on biological tissues and living organisms. (Suntharalingam et al, 2005, p. 485). The authors propose that radiobiology has two componential disciplines - radiation physics and biology. Thus, it is obvious now that to truly understand the full impact of this paper it is first necessary to know the basics of these two disciplines. Cellular Characteristics: All biological matter contains inorganic and organic compounds dissolved or suspended in water. This is protoplasm. The smallest structural and functional component of protoplasm that can exist freely is the cell (Suntharalingam et al, 2005, p. 485). It is just necessary to study the effects of radiation at the cellular level to truly understand the factors that affect biological tissues. Cells are of two types - somatic cells and germ cells. Of these somatic cells have three subtypes - stem cells (cells that generate other cells through differentiation), transit cells (cells that are in the state of being transformed from one type of cell to another) and mature cells (cells that are fully differentiated and are relatively stable in that state) (Suntharalingam et al, 2005, p. 487). Somatic cells proliferate through two well-defined time periods - mitosis (M), when cell division takes place while maintaining the species chromosome number; and the period of DNA synthesis (S). (Suntharalingam et al, 2005, p. 487). Before S, there is a gap (rest period) when DNA is not yet synthesized. After S there is another gap (when DNA is synthesized but other metabolic processes are taking place). After M takes place. Thus, the cell proliferation cycle is - S M. In time this whole process is - (1-8h) S (6-8h) (2-4h) M (>1h) (h = hours). Thus, the entire cell proliferation cycle can take between 10 to 20 hrs (Suntharalingam et al, 2005, p. 487). It is notable that cells are the most vulnerable to radiation (radiosensitive) in the M and phases while they are the most resistant in the late S phase (Suntharalingam et al, 2005, p. 487). When there is death among non-proliferating cells (static) there is said to be loss of a specific bodily function while death of proliferating cells such as stem cells and others are taken to be loss of reproductive integrity (Suntharalingam et al, 2005, p. 487). In cases where a certain radiation-damaged cell survives and begins to proliferate indefinitely it is termed as a 'clonogenic' cell (Suntharalingam et al, 2005, p. 487) with changed cellular characteristics (the change is to the DNA components of the cell). Radiation Characteristics: When cells are exposed to radiation the usual physical effects of the radiation on the atoms and molecules of the cells is immediate. Effects on biological function may follow later. Radiation effects on biological function are most pronounced when there is structural damage to DNA - the most critical target within cells (Suntharalingam et al, 2005, p. 488). It is obvious that some physical factor defines the quality of the ionizing radiation beam that may damage biological tissue. In radiobiology and radiation protection this physical factor is the 'linear energy transfer (LET). According to the ICRU it may be defined as - "LET of charged particles in a medium is the quotient dE/dl, where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dl." (Suntharalingam et al, 2005, p. 486) Thus, the impact that radiated packets may have with the atoms and molecules of the biological tissues is not as important as the amount of energy absorbed by the biological tissue components as the radiated packets pass through the biological tissues. This has some importance to note as impact energy may be in terms of MeV/cm while absorbed energy may be in terms of keV/M (Suntharalingam et al, 2005, p. 486). Some radiations are commonly used to combat tumourogenic cells. LET values for such radiations are as follows: 250 kVp X-rays: 2 keV/M Cobalt 60 rays: 0.3 keV/M 3 MeV X-rays: 0.3 keV/M 1 MeV electrons: 0.25 keV/M (Suntharalingam et al, 2005, p. 486). Radiation damage may be direct or indirect. Direct damage to cells is usually caused by radiation that induces high LET values and is a result of direct interaction with the critical target in the cells - the DNA. Indirect damage is usually caused by radiation that induces low LET values and where the critical target in the cells may be spared but other atoms and molecules in the cells such as water (water composes almost 80% of a cell) are irradiated. This results in formation of highly reactive free radicals like the and ions. These ions may subsequently react with the target and cause damage. Experimental Evidence: While it is noted that the paper has used a single publication to present the factors that may influence tissue response to radiation stress there are innumerable research papers presenting studies that experimentally prove that these previously presented factors due influence response to such stress. Now the paper shall posit some salient experimental studies that demonstrate that tissue response to radiation stress is a highly complex phenomenon and that simply positing these previously presented factors does not truly explain such responses. As is notable from the position of the paper, tissue response has to predict accurately cellular response, which is componential to such tissue response, to ionising radiation so that a workable pathological response can be set up to combat such stress (Barcellos-Hoff, 2005). It is noted that since ionising radiation deposits energy throughout the cell with direct effects that inflict immediate and extensive damage to macromolecules and DNA, initiate lipid peroxidation and protein oxidation while indirect effects include generation of highly reactive oxygen species (Barcellos-Hoff, 2005). Protein sensors within the cells immediately initiate a cellular response that seeks to determine whether the cell will be repaired and live or whether it should die. While this is true at the cellular levels, for an entire multicellular organism, grave implications of cellular death or dysfunction is only manifest with tissue and, subsequently, organ failure (Barcellos-Hoff, 2005). Essentially, multicellular organisms maintain a dichotomy of response mechanisms where there is a supracellular response mechanism in working in parallel to the cellular response (Barcellos-Hoff, 2005). It is observed that essential tissues such as bone marrow, the gastrointestinal tract and the central nervous system, intrinsic to organism survival, are very sensitive to radiation stress while many other tissues and organs, not considered that important for survival, are not so to that extent (Barcellos-Hoff, 2005). Essentially, this dichotomy of cellular response and tissue response creates a conflict where cell survival is pitted against tissue survival in many cases of radiation stress. This is when cell survival in the form of mutations threatens tissue functional status as tissue response may be construed as restricting damage and restoring homeostasis (Barcellos-Hoff, 2005). Some questions have to be answered in this context to accurately ascertain tissue responses in these situations. Which radiation-induced cytokines help restore homeostasis in the bone marrow What features of the irradiated tissue have long-term consequences and how are such consequences related to the radiation dosage How do stem cells respond and are their responses intrinsic or radiation-induced Do the progeny of irradiated cells inherit a certain phenotype and does this contribute to tissue dysfunction (Barcellos-Hoff, 2005) The p53 Sensor Mechanism: It is notable that the p53 DNA damage sensor mechanism works at the cellular level initiating apoptosis (growth arrest) under radiation stress (Komarova et al, 2000). Yet is also notable that many of the genes activated by the p53 system act in a tissue specific manner (Komarova et al, 2000). Thus, the paper notes that the previously mentioned dichotomy of cellular and tissue responses are not entirely exclusive but may be integrated to a greater extent than is now evident. This integrated approach may help to resolve to some extent the conflict between cell fate and tissue function. It is also notable that the p53 protein expression under stress in sensitive tissues is greater than in radiation resistant ones (Komarova et al, 2000). Thus, now it is simply notable here that the p53 initiated cell growth arrest is manifest most in sensitive tissue where maintaining tissue function surmounts cell fate. Another part of the tissue response system that also works at the cellular levels is the cytokine transforming growth factor-(TGF-) (Barcellos-Hoff, 2005). The factor is a part of the overall tissue response to stress and wounding and it also points to the possibilities that the tissue response to radiation stress is partly aligned to the cellular response making for a better overall integrated approach that increases the possibilities of maintaining tissue function and inhibiting organ failure - the main reason for death in cases of radiation stress. It is noted that the exact molecular mechanisms for both these integrated approaches are unavailable today in the sense that the exact manner in which the degree of cell fate is balanced with tissue function has not yet been either empirically or experimentally determined. Conclusion: This part is the conclusion to the paper's investigation of the factors that influence tissue response to radiation stress. It is notable that cellular response has been determined first here because, in essence, tissue response is a sum total of the entire information available from all the cells within the tissue and other related tissues and associated substances within the matrices determining a specific bodily function. Thus, the cellular part of this integrated system, the cells within the tissue and others outside, if severely enough damaged by the radiation, in a large part determines the effective tissue response and success in sustaining integrity of tissue function (Barcellos-Hoff, 2005). Thus, tissue response, like the cellular response posited earlier in the paper, depends upon the IR dose, dose rate, radiation quality and context (e.g. Genotype, age, pre-existing conditions) (Barcellos-Hoff, 2005) - factors entirely conformant with those of the cellular response. The next part of the paper shall investigate complicity due to radiation stress in a specific tissue. EBRT: Normal Tissue Complications The previous section of this paper has dealt a short account of how tissues and their componential cellular responses supplement radiation stress to biological matter. It is known that the very fact that radiation stress, in higher doses, induces apoptosis in afflicted cells is utilised to treat cancer cells. Selective doses administered to the mutant cells cause their death and relief to the patient. This is an extreme therapy and it is used only because there are often no other less aggressive palliative means of dealing with cancer. External Beam Radiation Therapy (EBRT): External beam radiation therapy (EBRT) is one such radiation therapy technique used to treat cancer cells. It uses linear accelerators to project high-energy external radiations that are then used to penetrate tissue and reach deep into the body where the cancer cells reside. It can be accurately projected at the cancer cells. Usually, instead of one large dose of radiation the patient is gradually, over a suitably long period of time, administered small doses that ultimately sum up to the effective dose, which may be too large for one single application. This is called dose fractionation. Even with this minimisation of the large dose into small ones it is often the case that adjacent normal cells and, consequently, tissue are also affected. This is normal tissue complication (Alektiar et al, 2005). While large dose implications to normal tissue may not be too clinically significant for older patients but paediatric patients with implicated normal developing tissue may be presented with possibilities of late complicacies and even second malignancies (DeLaney et al, 2005). Thus, treatment administrators are continuously presented with a twin set of problems - increase dosage to exterminate tumourous tissue but ensure least possible normal tissue complication. In the present, when there is no pervasive preventive treatment for cancer and also no pervasive long-term curative one radiation therapy remains one of the most effective palliative one where entire excision of the tumour is not possible. This is especially so for bone and soft tissue sarcomas where complete excision is not possible (Alektiar et al, 2005). Thus, with radiation therapy the only means of palliation remaining at the hands of the treatment administrator many strategies are utilised to keep the normal tissue from being implicated in the radiation therapy. One such strategy is dose fractionation when, for example: a 50 Gy dose is distributed into 2-3 Gy per session to minimise wound complications for normal tissue and allow treatment every day for 5 days a week. There is little need for recovery, as it is when large doses are administered and normal tissue complications have to be treated and healed before the next treatment can be arranged. It is the normal practice to minimise the radiation dose for normal tissue surrounding the tumourous one. The present technology allows smaller treatment volumes (with fractionated doses), reduction of normal tissue dose and volume irradiated, and a much more intense dose to the tumour cells. Three-dimensional (3-D) conformal techniques allow shaping of the dose around normal tissue, specifically organs, that need to remain unimplicated in the therapy (DeLaney et al, 2005). Computerisation of the entire process from treatment planning to dose administration has enabled all these yet wound complications for normal tissues are still associated when accessing certain tumour cells that require implication of normal tissue (DeLaney et al, 2005). Therapies with focused proton beams have enhanced clinical possibilities with minimum normal tissue implications yet soft and bone tissues continue to create problems when they harbour tumour cells in their midst (DeLaney et al, 2005). Modern imaging techniques like magnetic resonance imaging (MRI) and computed and positron emission tomography allow accurate mapping of the tumour topography that can later to utilised to focus radiation onto it sparing normal tissue maximally (DeLaney et al, 2005). This, together with a computerised treatment planning system that preferentially targets the tumour cells, allows maximum conformal radiation therapy. All radiation therapies alluded to earlier in this section are EBR (external beam radiation) type. Soft and Bone Tissue Complications: The paper shall now investigate how these vulnerable tissues get implicated in external beam radiation treatment of cancer cells. There is much evidential proof that EBR treatment to the musculoskeletal system, especially in small children in whom growth plates get implicated, often leads to long-term morbidities (Fletcher et al, 2004). Bone and soft tissue sarcomas require such fine limb salvaging techniques that the therapist is often defeated into compromising normal tissue at the expense of eliminating the sarcoma (Fletcher et al, 2004). The type and site of the sarcoma, the surgical approach adopted and the responses to chemotherapy determine whether EBR therapy will be neoadjuvant (pre-operative), adjuvant (post-operative) or simply local therapy (DeLaney et al, 2005). Neoadjuvant EBR therapy can be used for large and deep soft tissue sarcomas and before resection of spine and pelvic ones (DeLaney et al, 2005). Adjuvant EBR therapy can be used in patients with incompletely excised tumours and surgically contaminated tissues or where complete excision cannot be committed because of unsafe healthy normal tissue (at least 1 cm margin) margins or possibilities of compromising fascial planes (DeLaney et al, 2005). These are a few of the cases where sarcomas demand EBR therapy and there are many such cases with patient and sarcoma characteristics that require such therapy and this, in turn, presents innumerable possibilities of normal tissue complications in patients with such bone or soft tissue sarcomas. Such normal tissue complications for these special tissues show direct correlations to such variables as site (most important) and others (Alektiar et al, 2005). This is evident from what has been posited previously As the previous section on tissue and componential cellular responses to radiation stress demonstrates, such stress can instil mutant elements in the normal tissue that may have long-term implications. Thus, now the paper shall conclude with review of a particular radiation treatment process that promises prospects of least normal tissue complications. Conclusion Proton Beam Radiation: Common radiation techniques, EBR inclusive, use photons that gradually deposit their energy. This implies that, as the photons travel through the tissue masses of the patient during radiation treatment the energy is evenly distributed along the travel path of the photons. This, in turn, implies that, no matter how precise the tumour targeting is, any normal tissue in the path of the photon beams are automatically subjected to some amount of energy deposition. Some amount of LET (linear energy transfer) (Suntharalingam et al, 2005, p. 486) is implicated even for the normal tissue. A recent technique that utilises proton beams pre-empts this compromise as protons deposit their energy only when they near the end of their travel paths (DeLaney et al, 2005). The treatment, administrator can, thus, plan a proton trajectory that ends at the target cancer cells, thus allowing the protons to deposit maximum energy at this site. Care must be taken that the protons travel through normal tissue without deposition. This can be ensured by accelerating the protons with just enough energy to travel to the innermost part of the cancer site (DeLaney et al, 2005). Thus, with maximal LET for the tumour cells and minimal LET for normal non-target cells proton radiation may be the most appropriate radiation technique for this sort of therapy. It is noted here that protons are heavier than photons and any negative effects of this larger mass may be scrutinised further to allow safe usage of this radiation technique. References: Alektiar, Kaled M., et al, Influence of Site on the Therapeutic Ratio of Adjuvant Radiotherapy in Soft-Tissue Sarcoma in the Extremity, Int. J. Radiation Oncology Biol. Phys. Vol. 63, No. 1, pp. 202-208, 2005. Barcellos-Hoff, M H., How tissues respond to damage at the cellular level: orchestration by the transforming growth factor- (TGF-), British Journal of Radiology (2005), Supplement 27; 123-127. DeLaney, Thomas F., et al, Advanced-Technology Radiation Therapy in the Management of Soft and Bone Tissue Sarcomas, Cancer Control, 2005; 12(1); 27-35. Fletcher, Daniel T., et al, Valgus and varus deformity after wide-local excision, brachytherapy and external beam irradiation in tow children with lower extremity synovial cell sarcoma: case report, BMC Cancer 2004; 4:57. Komarova, Elena A., et al, Different impact of p53 and p21 on the radiation response of mouse tissues, Oncogene (2000) 19; 3791-3798. N. Suntharalingam, E.B. Podgorsak, J.H. Hendry, Basic radiobiology, in "Radiation Oncology Physics: A Handbook for Teachers and students", Chapter 14, pp. 485-504, edited by E.B. Podgorsak, International Atomic Energy Agency, Vienna, Austria (2005). Read More