Question

sketch and label two cell survival curves (on the same set of labeled axes)-- one curve for a group of cells that are relatively sensitive to radiation, and the other for a group of cells that are relatively resistant to radiation

Answer 1

Radiobiology and radiation protection the physical quantity that is useful for defining the quality of an ionizing radiation beam is the linear energy transfer (LET). In contrast to the stopping power that focuses attention on the energy loss by an energetic charged particle moving through a medium, the LET focuses attention on the linear rate of energy absorption by the absorbing medium as the charged particle traverses the medium.

Cells are least sensitive when in the S phase, then the G₁ phase, then the G₂ phase, and most sensitive in the M phase of the cell cycle. This is described by the 'law of Bergonié and Tribondeau', formulated in 1906: X-rays are more effective on cells which have a greater reproductive activity.^[1][2]

From their observations, they concluded that quickly dividing tumor cells are generally more sensitive than the majority of body cells. This is not always true. Tumor cells can be hypoxic and therefore less sensitive to X-rays because most of their effects are mediated by the free radicals produced by ionizing oxygen.

It has meanwhile been shown that the most sensitive cells are those that are undifferentiated, well nourished, dividing quickly and highly active metabolically. Amongst the body cells, the most sensitive are spermatogonia and erythroblasts, epidermal stem cells, gastrointestinal stem cells.^[3] The least sensitive are nerve cells and muscle fibers.

The International Commission on Radiological Units and Measurements (ICRU) defines the LET as follows: "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". In contrast to the stopping power with a typical unit of MeV/cm, the unit usually used for the LET is keV /µ m

. The energy average is obtained by dividing the particle track into equal energy increments and averaging the length of track over which these energy increments are deposited. • Typical LET values for commonly used radiations are: - 250 kVp x ray : 2 keV /µ m - cobalt-60 gamma ray : 0.3 keV/µ m - 3 MeV x ray : 0.3 keV/µ m - 1 MeV electron : 0.25 keV/µ m • Values for other less commonly used radiations are: - 14 MeV neutrons : 12 keV/µ m - heavy charged particles : 100-200 keV/µ m - 1 keV electron : 12.3 keV/µ m - 10 keV electron : 2.3 keV/µ m 398 Review of Radiation Oncology Physics: A Handbook for Teachers and Students X rays and gamma rays are considered low LET (sparsely ionizing) radiations, while energetic neutrons, protons and heavy charged particles are high LET (densely ionizing) radiations. The demarcation value between low and high LET is at about 10 keV/µ m.

Another major focus in the study of radiosensitivity in vitro has been to identify genes that associate with cellular response to radiation. Studies have focused on genes that determine efficacy of DNA repair [8] and more recently on TP53. Tumor cells mutant in TP53 have elevated prevalence in human tumors, and the TP53 gene has have been suggested as important in radiation response [9]. Radiosensitivity in cells that vary in TP53 status has been extensively studied and reviewed comparing radiosensitivity with TP53 status [1013]. In general these reviews conclude that there is an association between cellular radiosensitivity and TP53 status or p53 protein synthesis but this is not a universal finding. For instance Daniels et al. [14] find no association between TP53 status and p53 synthesis in human melanoma lines. Important for this paper is the observation by Kandolier et al. [15] that there is an association between TP53 status but not p53 protein of tumor cells and the clinical response of rectal cancer to local preoperative radiotherapy. The mechanistic bases for involvement of TP53 in cellular radiosensitivity have not been identified, complicated by multiple roles that TP53 plays in the cell

IRRADIATION OF CELLS When cells are exposed to ionizing radiation the standard physical effects between radiation and atoms or molecules of the cells occur first and the possible biological damage to cell functions follows later. The biological effects of radiation result mainly from damage to the DNA which is the most critical target within the cell; however, there are also other sites in the cell which, when damaged, may lead to cell death. When directly ionizing radiation is absorbed in biological material, the damage to the cell may occur in one of two ways: direct or indirect action. 14.4.1. Direct action in cell damage by radiation In direct action the radiation interacts directly with the critical target in the cell. The atoms of the target itself may be ionized or excited through Coulomb interactions leading to the chain of physical and chemical events that eventually produce the biological damage. Direct action is the dominant process in interaction of high LET particles with biological aspect

other for a group of cells that are relatively resistant to radiation

Mechanisms of Radiosensitivity and Radioresistance

Effect of radiation on clonogenic or tumor stem cells

In radiation biology, clonogenic tumor cells have been defined as cells that have the capacity to produce an expanding family of daughter cells and form colonies following irradiation in an in-vitro assay or give rise to a recurrent tumor in in-vivo models. Whether clonogenic cells fully represent tumor stem cells is unclear but more recently the terms have been used interchangeably^5,6. The goal of radiation therapy in curative intent is to eradicate the last surviving tumor stem cell, as a single stem cell remaining after completion of treatment may give rise to a local tumor recurrence (reviewed in ⁴). Radiation-induced cell killing (or radiobiologically called cell “inactivation”) is random: lethal unrepairable DNA double-strand breaks (DSB) are generated randomly in a cell population of similar cellular radiosensitivity, at low doses eradicating some but not all stem cells. Increasing the radiation dose, for a given number of tumor stem cells, will lead to higher odds that a stem cell gets hit with at least one lethal event, thereby decreasing the number of surviving cells

s are sparse but generally suggest a greater intrinsic radioresistance of stem cells⁶.

Figure 1

Figure 2

Incorporation of EGFR-directed agents with radiation in the treatment of locally advanced NSCLC. RT, radiation therapy; mAb, monoclonal antibody; TKI, tyrosine kinase inhibitor; wt, wild-type; mut, mutant

The problem of accelerated tumor cell repopulation

Biological effects of radiation are typically divided into two categories. The first category consists of exposure to high doses of radiation over short periods of time producing acute or short term effects. The second category represents exposure to low doses of radiation over an extended period of time producing chronic or long term effects. High doses tend to kill cells, while low doses tend to damage or change them. High doses can kill so many cells that tissues and organs are damaged. This in turn may cause a rapid whole body response often called the Acute Radiation Syndrome (ARS). High dose effects are discussed on pages 6-12 to 6- 16. Low doses spread out over long periods of time don’t cause an immediate problem to any body organ.