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Survival curves

The radiosensitivity of healthy cells or tumour cells can be determined by the preparation of survival curves after irradiation, and for cancer cells, at best using in vitro clonogenic culture (study of stem cells).

The curve which is obtained can be transformed into a mathematical model giving the proportion of surviving cells after irradiation. The mathematical model which correlates at best with the experimental curves for mammalian cells is a linear quadratic model, or ballistic model:

where S is the survival at the dose D and α and β are two coefficients. In semilogarithmic coordinates, the curve is biphasic with an initial linear portion, then a shoulder, then a distal linear portion.

Thanks to modelling of survival curves, it is possible to formulate various hypotheses concerning the cell death induced by ionising radiation. According to this linear quadratic model, cell death can be in relation to:

• lethal lesions which cannot be repaired (αD component of the survival curve)
  
• the accumulation of sublethal lesions (β component of the survival curve); experimentally, the survival is increased when the irradiation dose is divided into two fractions separated by a time interval of around 6 hours, which is sufficient to enable the repair mechanisms to operate.
  
• the non-reparation of potentially lethal lesions; these are repairable lesions, which can actually occur if, after irradiation, the cells are maintained in culture conditions delaying the progression of the cell cycle; for example confluence, depletion of growth factors or incubation with inhibitors of DNA synthesis. On the contrary, the reparation of potentially lethal lesions is activated by βFGF in certain cell lines.

Various parameters can be calculated from this equation to characterise radiosensitivity: the SF2 (Survival Fraction at 2 Gy) is most frequently is used. The greater the SF2 value, the less sensitive the cell line is to radiotherapy.

Variations in the radiosensitivity

Radiosensitivity varies from one cell line to another; haematopoietic stem cells and germinal stem cells are among the most radiosensitive. In general, the poorer a cell’s differentiation, the more radiosensitive it is.

For the same cell line, radiosensitivity varies according to:

Cell characteristics

• position of the cells in the cell cycle cell cycle, the G2 and M phases are the most radiosensitive,
  
• the oxygenation tension ,
  
• pH,
  
• the DNA content, in
  
• the glutathione and thiol content,
  
• the repair system efficiency after radio-induced lesions.
  

Parameters in relation with the irradiation technique

• § role of Linear Energy Transfer. This value characterises the ionisation density in a unit of the path depth. The higher the LET, the greater the lethality due to the increased difficulty in repairing induced lesions,
  .
• fractionating and staggering of the dose (dose flow rate): when cells are irradiated with a low rate, they can repair their sublethal lesions during irradiation, eliminating the β component with a linear survival curve with a single α slope.

The in vitro determination of SF2 or of D0 (the prolongation of the distal slope of the survival curve) does not systematically predict in vivo radiosensitivity, i.e. cure by radiation. In reality the D0 of tumour cell lines is not very different from the D0 of normal fibroblasts and the in vitro radiosensitivity of tumour cells from an in vivo non sensitive tumour is similar to the sensitivity of cells issued from radiocurable tumours.

Many hypotheses have been formulated concerning this discrepancy between in vitro radiosensitivity and in vivo radiocurability:

• modification of the cell properties due to in vitro culture (lack of growth factors, need for specific tissue culture supports),
  
• in vivo selection by ionising radiation of radioresistant cells,
  
• in vivo induction of mutations by ionising radiation giving birth to a few radioresistant cells amidst a radiosensitive population,
  
• role of the stroma which is a support for the tumour, with its various cells (endothelial cells, lymphocytes, macrophages) able to secrete various cytokines modulating the radio-sensitivity like Tumor Necrosis Factor or Fibroblast Growth Factor.
• role of the stroma which is a support for the tumour, with its various cells (endothelial cells, lymphocytes, macrophages) able to secrete various cytokines modulating radiosensitivity, such as α Tumor Necrosis Factor or β Fibroblast Growth Factor.