International Journal of Radiation Biology

ISSN: 0955-3002 (Print) 1362-3095 (Online) Journal homepage: http://www.tandfonline.com/loi/irab20

The 5Rs of Radiobiology

G. Gordon Steel, T.J. McMillan & J.H. Peacock
To cite this article: G. Gordon Steel, T.J. McMillan & J.H. Peacock (1989) The 5Rs of
Radiobiology, International Journal of Radiation Biology, 56:6, 1045-1048
To link to this article: http://dx.doi.org/10.1080/09553008914552491

Published online: 03 Jul 2009.

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INT . J . RADIAT . BIOL ., 1989, VOL 56, NO . 6, 1 04 5-1048

Letter to the Editor

The 5Rs of Radiobiology

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(Received 24 July 1989)

In 1975 Rod Withers published a paper entitled `The 4 R's of Radiotherapy'

(sic .) . In spite of its ungrammatical apostrophe, this title neatly encapsulated a short
list of mechanisms that are important in determining the response of a biological
tissue to multiple doses of radiation : Repair, Reassortment, Repopulation, Reoxygenation . One or more of these factors, said Withers, may account for the greater
sparing of normal tissues than tumours by fractionated radiotherapy . And year by
year young radiotherapists are taught to cite them in answer to almost any
radiobiological question that they may encounter in their qualifying examination .
Developments during the 1980s in our understanding of the radiobiology of
human tumours have led to the realization that cells from different types of tumour
differ markedly in their inherent radiosensitivity, i .e . in the steepness of the oxic cell
survival curve . This was shown for the initial part of the survival curve by Fertil
and Malaise (1981) in their survey of published data, and it was confirmed by
ourselves (Deacon et al . 1984) . Cell lines established from tumours that are
clinically responsive to radiotherapy had a significantly steeper initial slope than
those from less curable tumours, as indicated by the survival fraction at 2 Gy .
Subsequent work on a representative group of human tumour cell lines has
confirmed that the differences in the oxic cell survival curves among human
tumours are considerable, and quite large enough by themselves to explain the
clinically observed differences in curability (Steel et al . 1987) .
We have also found that at low dose rate the differences in radiosensitivity
between human tumour cell lines are even greater . This is illustrated in figure 1 for
four particular cell lines (see Steel et al . 1987 for further examples) . We have argued
that the low-dose-rate survival curves in figure 1B convey a more clinically relevant
picture of the inter-tumour differences than do the acute survival curves . If one
assumes that in fractionated radiotherapy the surviving fraction per dose is that
seen in the acute survival curve, and that it is constant throughout the course of
treatment, then a series of 2 Gy doses would give linear survival curves that range as
widely as those shown in figure 1B . The argument is even clearer in the case of
interstitial or intracavitary radiotherapy : the relevant survival curves are those
obtained at low dose rate .
It might be thought that the large differences among the survival curves at low
dose rate reflect a different extent of repair among the cell lines, but this may not be
so . For a cell line derived from a human melanoma, figure 2 shows cell survival data
at three dose rates : 150, 7 . 5 and 1 . 6 cGy/min . The data have been simultaneously
fitted with the lethal-potentially lethal damage (LPL) model of Curtis (1986) . This
model fits the data reasonably well, and it allows us to deduce two theoretical lines .
0020-7616/89 $3 .00 1989 Taylor & Francis Ltd

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1 04 6

Letter to the Editor

Figure 1 . Cell survival curves for four human tumour cell lines : HX142 (neuroblastoma) ;
HX58 (pancreatic ca .) ; HX156 (cervix ca .) ; RT112 (bladder ca .) . A : At high dose rate
(approx . 150 cGy/min) ; B : at low dose rate (approx . 2 cGy/min) . Data from Steel et al.
(1987) and unpublished data of J . H . Peacock .
Line A is the predicted survival curve when repair has gone to completion . The
slope of this line reflects the idea that even under conditions of maximal repair there
are some lesions that remain unrepaired . Line B is the predicted survival curve in
the total absence of repair, where every initially induced lesion is lethal . The
observed survivals at 1 . 6 cGy/min and the high-dose-rate points at and below 2 Gy
are close to the fully repaired line A . 'Phis model therefore implies that under these
conditions the effect of recovery is to increase survival from that given by line B
almost up to that given by line A : potentially lethal lesions are almost fully repaired
and contribute little to cell killing . A similar conclusion may be drawn from the
earlier work of Pohlit and Heyder (1981) which predated the LPL model .
If this view is correct then the range of sensitivities seen at low dose rate in
figure 1 may well not be due to different repair, but to differences in the sensitivity
of the cells to the direct infliction of non-repairable lesions (Steel and Peacock,
1989) . This conclusion is not restricted to the LPL model . Simulation of a finite
initial slope requires the assumption of a component of non-repairable damage also
in other prominent models : the multi-target with single-hit model (Bender and
Gooch, 1962), and the Q-repair model of Alper (1979) . The repair-misrepair model
of Tobias (1985) envisages that the linear component arises from the 'selfmisrepair' of a proportion of lesions, each of which then leads to cell death . The
steepness of the linear component of cell killing varies by a factor of 10 among
human tumour cells, and is the main determinant of low-dose sensitivity (Steel
et al . 1987) .
The term `radiosensitivity' can therefore have a number of meanings . The most
direct is the steepness of the acute radiation survival curve . As argued above, a more

Letter to the Editor

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Figure 2 . Cell survival curves for a human melanoma cell line (HX118) irradiated at 150,
7 . 6 or 1 . 6 cGy/min . The data are fitted by the LPL model (full lines) from which are
derived the survival curve where repair is complete (curve A) or where repair is totally
absent (curve B) . Redrawn from Kelland and Steel (1986) .
clinically relevant meaning is the survival curve at low dose rate, which may
approximate the initial slope of the acute cell survival curve . A third meaning might
be the sensitivity for the initial induction of damage (i .e . curve B) . The difference
between curve B and the survival curve observed at high dose rate may be described
as due to `unstoppable recovery', i .e . recovery that occurs during the performance
of an immediate cell survival assay . There is no agreed way of determining curve B,
but if one takes the initial incidence of DNA damage as an indication of its relative
position among different cell lines, then there are some data which suggest that this
varies as widely as the acute survival curve itself (Radford 1986, Kelland et al. 1988,
Cassoni and McMillan, unpublished) . The contributions of initial damage or repair
to overall radiosensitivity have recently been discussed by Peacock et al . (1989) .
Although these aspects of the fundamental nature of radiosensitivity are
controversial, the point that we wish to indicate is that radiosensitivity deserves to
be listed as a determinant of response (in tumours or in normal tissues) by whatever
meaning of the term one might choose . We should therefore teach the five Rs of
radiotherapy rather than the four . And in asking why radiotherapy succeeds with
some tumours and not with others we would be inclined to favour the fifth R :
radiosensitivity .
G . GORDON STEEL, T . J . MCMILLAN and J . H . PEACOCK
Radiotherapy Research Unit, Institute of Cancer Research,
Sutton, Surrey SM2 SPX, U.K .

1048

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