Medical Archive

Hall C19 Dose-Response Relationships for Model Normal Tissues

1 Dose-response relationships

– Absorbed dose ∝ incidence, severity of radiation effect
– Absorbed dose and incidence curve: sigmoid shape (tumor control, normal-tissue complication)

2 Therapeutic ratio (therapeutic index)

 – The ratio of the tumor response for a fixed level of normal-tissue damage
 – The addition of a drug, a chemotherapy agent or a radiosensitizer, moves the tumor control curve to the left farther than the normal tissue damage curve à therapeutic gain. (Figure 19.2)

3 Types of cell death: How and Why cell die

– Mitotic linked cell death, necrotic death, apoptotic death, autophagic death, bystander induced death

– Mitotic-linked cell death and apoptotic cell death are responsible for most cell killing by radiation

a. mitotic death: die attempting to divide, does not necessarily occur at the first post irradiation mitosis

– apoptosis: programmed cell death, cell condensation, membrane-enclosed bodies are phagocytized by nearby tissue cell
affects scattered individual cells à no tissue disorganization that occurs after necrosis

4 Assays for dose-response relationships

Clonogenic end points

    a. clones regrowing in situ

: skin colony, regenerating crypts in the jejunum, testes stem cell, kidney tubule

    b. cells transplanted to another site

        :can manipulate the physiologic states of donor or recipient animals hormonally

        : bone marrow stem cell, mammary and thyroid cell

   – Functional end points

     a. skin (pig, rodent, etc)

breathing rate (early and late response of the lung)

spinal cord myelopathy

– Inferring the ratio alpha/beta

5 Clonogenic end points

1) Clones regrowing in situ

a. skin colony: by Withers, 30 Gy of 30-kv x ray, moat, test dose,

– Technique (Figure 19.3)

D0=1.35 Gy à similar to the value obtained with mammalian cells cultured in vitro

Dq=3.5 Gy à similar to the value for human skin estimated from split-dose experiments

– Limitation:

  • range in which the dose-response relationship can be determined (8~25 Gy)
  • we don’t know how many skin stem cells there are per unit area

b. Crypt cells of the mouse jejunum

– by Withers and Elkind, regenerating crypts per circumference of the sectioned jejunum

– Technique

total body irradiation to animals àsterilizes a significant proportion of the dividing cells in the crypts à after 3.5 days, sections of the jejunum are made à the number of regenerating crypts per circumference is scored.

– Limitation (Figure 19.8)

  • the quantity plotted on the ordinate is not the surviving fraction
  • experiments can be done only at doses of about 10 Gy or more
  • -> sufficient level of biologic damage to be identified

c. Testes stem cells

– by Withers, et al, 6 weeks after irradiation, the proportion of tubules containing spermatogenic epithelium

– 8-16 Gy, D0=1.68 Gy, Dq=2.7 Gy by split-dose tech., reconstruction of survival curve (Figure 19.11, 19.12)

d. Kidney tubule

– by Withers, et al, the first clonal assay for a late-responding tissue,

– Technique

Irradiation to one kidney per mouse with small field à histologic examination after 60 weeks – The radiosensitivity of late responding tissue is not very different from that of early-responding tissues, such as the skin or intestinal epithelium. The rate of response, however, is quite different. (The time required for depletion of the epithelium after a single dose of 14 Gy: 3 days for jejunum, 24 days for the skin, 30 days for the seminiferous tubules 300 days for the kidney tubules) à the slow expression of injury merely reflects the slow turnover of cell population

2) Cells transplanted to another site

a. bone marrow stem cell

– by Till and McCulloch, a survival curve for colony-forming bone marrow cells

– Technique

  • Supralethal radiation with dose of 9 ~10 Gy sterilized spleens of recipient animals
  • A donor animal is irradiated to some test dose
  • The suspension of cells from the bone marrow is inoculated into recipient animals
  • This procedure is repeated for a range of doses à a survival curve is obtained.

  – Bone marrow stem cells are very sensitive with a D0 of about 0.95 Gy (Figure 19.17)

b. Mammary and thyroid cells

– Technique

  • irradiated in vivo à cell suspension
  • inject into the inguinal or interscapular white fat pads of recipient animal
  • count mammary or thyroid structures 3.5 weeks after injection

3) Summary of survival curves for clonogenic assays of cells from normal tissues

– The width of the shoulder of the curve is the principal variable.

Jejunal crypt cells have a very large shoulder; bone-marrow stem cells have little

6 Dose-response relationships for functional end points

a. Pig skin

– many features are in common with human skin

– can be extrapolated to the human with a high degree of confidence

– pioneered by Flowler and colleagues, scoring of skin reaction after irradiation

– two phase reaction (early reactionà erythema, etc, late reactionà contraction, etc)

b. Rodent skin

– Mouse leg and foot (one hind leg à experiment, the other leg à control)

– appear by about the 10th days and peaked by 20 to 25 days (Figure 19.23)

– Second wave of the reaction: not observed in mice, but in rat.

c. Breathing rate

– Breathing frequency increases progressively with dose after a threshold of about 11 Gy (Figure 19.24)

– Early response (16-36 weeks, pneumonitis), late response (by 52 weeks, fibrosis)

– A simple but highly quantitative and reproducible system

d. spinal cord myelopathy

  • The various syndromes of radiation-induced injury in rodent brain and spinal cord are very similar to those described in humans
  • Latent periods of 4-12 months
  • Cause of damage
    • within first 6 months: white matter damage (focal or diffuse demyelination and necrosis)
    • late delayed injury peaks at 1 to 2 years postirradation :
      • common type: vascular basis
      • another type: slowly progressive glial atrophy
  • Latency: the general tendency is a decreasing latency with increases in dose of approximately 2 days/Gy
  • Fractionation and protraction
    • dramatic sparing from fractionation
    • interfraction time less than 4 hours à incomplete repair
      if multiple doses per day are used to the spinal cord, the interfraction interval should be at least 6 to 8 hours
  • Volume effect:

 ① Spinal cord : functional subunits (FSUs) are arranged in linear fashion

② marked dependence of spinal cord length below 1cm (Figure 19.27)

③ Beyond a few centimeters, the tolerance is virtually independent of length of cord

  • Retreatment after long time intervals
    • The extent of recovery depends on the first treatment
    • Experiments with rats: After an initial treatment to 50% tolerance, the retreatment tolerance approaches 90% of the tolerance of the untreated control group by about a year after the initial irradiation





7 Inferring the ratio α/β from multifraction experiments in nonclonogenic systems





a. Assumption





    

  1. linear-quadratic model
    2. 




  2. each dose in a fractionated regimen produces the same biologic effect
    3. 




  3. full repair of sublethal damage takes place between dose fractions, but no cell proliferation occurs  
    4. 






b. Suppose the total dose, D, is divided into n equal fractions of D.





         















   (1/nd) is plotted against the dose per fraction (d)





c. α/β ratio tends to be larger for early-responding tissues, about 10 Gy, than for late-responding tissues, about 2 Gy.







김경수교수님 ROJ paper
breast cancer, brain mets
* Radiobiologic consideration > dose-fx이 다른 여러 trial을 바탕으로 점을 찍어서 alpha/beta ratio를 구할 수 있다. 이런식으로 측정한다는 것을 보면 좋음.