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X- or γ-ray leukemogenesis in humans
Medical Hypotheses 7:
111-114, 1981
X- OR Y-RAY LEDKEMOGENESIS IN HUMANS P. Rosen, Hasbrouck Laboratory, University of Massachusetts, Amherst, Massachusetts 01003, U.S.A. ABSTRACT A calculation of the probability of X-ray or y-ray leukemogenesis per cell in humans is made. It is assumed that the theory is of the twohit type. The first hit damages DNA repair capability of base damage. The second hit causes derepression of a 2 repressor system. Sequential repression of gene expression occurs. Inactivation of the first repressor permits synthesis of the second which will repress the expression of the leukocyte maturation gene. The first repressor is inactivated by X-ray damage to its corresponding operator region. I have used a more realistic value of irmnuneefficiency for the bone marrow and I have considered spontaneous leukemogenesis. Agreement with the best algebraic fit of Kellerer and Rossi for the Nagasaki victims is good, Key words.
Leukemia, X-ray, y-ray, Nagasaki, atom bomb INTRODUCTION
In a previous paper I (1) have attempted to explain theoretically the probability of leukemogenesis in the human population at Nagasaki. The data have been analyzed by Kellerer and Rossi (2). Starting from the mutation frequency of Abrahamson et al (3), I would like to improve on my original calculation by including a) spontaneous incidence and b) a more realistic value for immuneefficiency in the bone marrow than a mere average value for the entire body. c) removing from consideration double strand breaks because they represent much lower probabilities and d) using a best fit experimental formula (2) for comparison. I assume a two-hit theory in which DNA damage occurs first in a gene specifying premutational repair and the second hit causes the leukemic state. The leukemic state is one in which a leukocyte does not possess the maturation protein MGI (4). IONIZING RADIATION DAMAGE TO DNA The two types of damage for ionizing radiation are base damage (5) and double strand breaks (6). I shall justify the use of base damage alone in this problem. For humans (3) the mutation frequency per locus
111
per rad in gametes is approximately 2.6x10-1. Some of this is caused by double strand breaks. For example Corry and Cole (6) give an average value of .32 double strand breaks (d.s.b.) per cell rad. For humans this yields a value of 6.7 x10 -11 d.s.b./rad base pair (B.P.,), since the human genome DNA is 5.8 picograms (3). Since repair is negligible for the gametes and the mutation frequency per unexcised double strand break is of the order of unity with an average gene size of 1000 base pairs long (7) the contribution to mutation of the d.s.b. is about 6~10~~. One type of base damage, the t' base damage repair extremely well in mammals(8). We interpret the remaining value 2~10~~ on the curve of Abrahamson et al (3) as mainly due to base damage. I emphasize this because the value for humans is an extrapolation. LEUKEMOGENESIS We assume the following scenario: a combination of two repressors (8) can account for a sequential repression of gene expression. Inactivation of the first repressor permits synthesis of the second which will repress the expression of the leukocyte maturation gene. The first repressor is inactivated by X-ray damage to its correponding operator region. If the average gene size is L base pairs and the size of the critical operator region is L , then the probability of leukemogenesis per cell in humans will be gyven by: _V D 2Lo 2 p37 P=Po+F LD e (1-I) (1) where PO is the spontaneous probability, F is the mutation induction freis 37% quency per locus (of size L) per rad, D is the dose in rads, D survival dose and I is the immunological efficiency. I is def&?ed as the fraction of initially transformed cells that are removed by the immune system. rad-' and for I take L=lOOO B,P,(7), Lo=20 B.P., F=2x10s7 haemotopoetic cells D37=100 rads (10). The value of (1-I) for the reticuloendothelial system is & (ll), I assume this value of l-1 applies to the bone marrow as well. The number of marrow cells per person is taken as 6.7 ~10~~ (12). The best approximation (2) to the data for survivors at Nagasaki is given by the equation I = 4.8x10
-4
+ 807x10
-8 D2
(2)
If we wish the theoretical value of P we have: P=7,2
x
lo-l6 + (2~10~~)~ $&j
D2 e- hi
(3a)
or P=7.2x10-16+2.67x10-18
D2 d- i%i
(3b)
This is to be compared with the experimentally observed value Px = 7.2x10-l6 + 1.3 x 10-l' D2 112
(4)
We can now compare the experimental values at various doses. This is shown in Table I. Table I.
Probability
Dose
(rads)
of Leukemogenesis
for theoretical
per Cell at Different
P
P
Doses
Calc.
0
7.2 xX10-16
7.2 x 10
5
7.5 x lo-l6
7,8 x 10
-15
values
-16 -16 -15
150
3.7 x 10
300
1.2 x lo-l4
1.3 x 10
400
2.1 x lo-l4
8.4 x lo-l5
2.2 x 10
-14
CONCLUSION I have considered a two-hit theory of X or y-ray leukemogenesis in which the first hit inactivates excision repair of base damage and the second hit causes the derepression of the first of a two operator system such that the substance MGI can not be made. This causes the leukemic state in which leukocytes do not mature. The agreement between theory and the observed results from the victims of Nagasaki is good. It may be possible that at high doses of the order of 400 rads, the factor (1 - I) is affected so that-the calculated incidence is higher than expected. REFERENCES 1.
Rosen P. X- or y-ray leukemogenesis cal Biology 75:603, 1979,
2.
Kellerer A M, and Rossi HH. Biophysical aspects of radiation carcinogenesis. P405 in Cancer 1. A comprehensive Treatise, Chemical and Physical Carcinogenesis (F.F, Becker ed.) Plenum Press, Nyew York, (1975).
3.
Abrahamson S, Bender MA, Conger AD, and Wolff S. Uniformity of radiation induced mutation rates among different species. Nature 245: 460, 1973.
4,
Sachs L. Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature 274~535, 1918.
5.
Cerruti P. and Renson JF. Gamma ray excision repair in normal and diseased human cells. P93 in Biology of Radiation Carcinogenesis. (J.M. Yuhas, R.W. Tennant and J,D. Regan eds,) Raven Press, New York 1976.
6.
Corry PM and Cole A. Double strand rejoining Nature 245:100, 1973,
7.
Maniantis F, Efstradiadis A, Sim GK, and Kafatos F. Amplification and characterization of eukaryotic structural genes. P9 in Third Decennial Review Conference: Cell, Tissue and Organ Culture, (Gene Expression and Regulation in Cultured Cells) National Cancer Institute
113
in humans.
Journal of Theoreti-
in mammalian
DNA,
Monograph 48, 1978. 8.
Mattern MR, Hariharan PV, and Cerruti PA. Selective excision of gamma ray damaged thymine from the DNA of cultured mammalian cells. Biochimica et Biophysics Acta 395:48, 1975.
9.
Kourilsky P and Grof F. Genetic control of transcription. Pl9 in Regulation of Gene Expression in Eukaryotic Cells (M. Harris and B. Thompson, eds.) U.S. Government Printing Office: D.H.E.W. Publication NO (NIH) 74-648, 1973.
10.
Mole RH. Ionizing radiation as a carcinogen: practical questions and academic pursuits. British Journal of Radiology 48:157, 1975,
11.
Pitot HC. Fundamentals of Oncology.
12.
Mole RH. Carcinogenesis by ionizing radiation and lessons for other pollutants. P860 in Radiation Research, Proceedings of the Fifth International Congress of Radiation Research. Seattle. (O.F. Nygaard, H,L. Adler and W,K, Sinclair eds.) Academic Press, New York, 1975.
114
Marcel Dekker, New York 1978.
111-114, 1981
X- OR Y-RAY LEDKEMOGENESIS IN HUMANS P. Rosen, Hasbrouck Laboratory, University of Massachusetts, Amherst, Massachusetts 01003, U.S.A. ABSTRACT A calculation of the probability of X-ray or y-ray leukemogenesis per cell in humans is made. It is assumed that the theory is of the twohit type. The first hit damages DNA repair capability of base damage. The second hit causes derepression of a 2 repressor system. Sequential repression of gene expression occurs. Inactivation of the first repressor permits synthesis of the second which will repress the expression of the leukocyte maturation gene. The first repressor is inactivated by X-ray damage to its corresponding operator region. I have used a more realistic value of irmnuneefficiency for the bone marrow and I have considered spontaneous leukemogenesis. Agreement with the best algebraic fit of Kellerer and Rossi for the Nagasaki victims is good, Key words.
Leukemia, X-ray, y-ray, Nagasaki, atom bomb INTRODUCTION
In a previous paper I (1) have attempted to explain theoretically the probability of leukemogenesis in the human population at Nagasaki. The data have been analyzed by Kellerer and Rossi (2). Starting from the mutation frequency of Abrahamson et al (3), I would like to improve on my original calculation by including a) spontaneous incidence and b) a more realistic value for immuneefficiency in the bone marrow than a mere average value for the entire body. c) removing from consideration double strand breaks because they represent much lower probabilities and d) using a best fit experimental formula (2) for comparison. I assume a two-hit theory in which DNA damage occurs first in a gene specifying premutational repair and the second hit causes the leukemic state. The leukemic state is one in which a leukocyte does not possess the maturation protein MGI (4). IONIZING RADIATION DAMAGE TO DNA The two types of damage for ionizing radiation are base damage (5) and double strand breaks (6). I shall justify the use of base damage alone in this problem. For humans (3) the mutation frequency per locus
111
per rad in gametes is approximately 2.6x10-1. Some of this is caused by double strand breaks. For example Corry and Cole (6) give an average value of .32 double strand breaks (d.s.b.) per cell rad. For humans this yields a value of 6.7 x10 -11 d.s.b./rad base pair (B.P.,), since the human genome DNA is 5.8 picograms (3). Since repair is negligible for the gametes and the mutation frequency per unexcised double strand break is of the order of unity with an average gene size of 1000 base pairs long (7) the contribution to mutation of the d.s.b. is about 6~10~~. One type of base damage, the t' base damage repair extremely well in mammals(8). We interpret the remaining value 2~10~~ on the curve of Abrahamson et al (3) as mainly due to base damage. I emphasize this because the value for humans is an extrapolation. LEUKEMOGENESIS We assume the following scenario: a combination of two repressors (8) can account for a sequential repression of gene expression. Inactivation of the first repressor permits synthesis of the second which will repress the expression of the leukocyte maturation gene. The first repressor is inactivated by X-ray damage to its correponding operator region. If the average gene size is L base pairs and the size of the critical operator region is L , then the probability of leukemogenesis per cell in humans will be gyven by: _V D 2Lo 2 p37 P=Po+F LD e (1-I) (1) where PO is the spontaneous probability, F is the mutation induction freis 37% quency per locus (of size L) per rad, D is the dose in rads, D survival dose and I is the immunological efficiency. I is def&?ed as the fraction of initially transformed cells that are removed by the immune system. rad-' and for I take L=lOOO B,P,(7), Lo=20 B.P., F=2x10s7 haemotopoetic cells D37=100 rads (10). The value of (1-I) for the reticuloendothelial system is & (ll), I assume this value of l-1 applies to the bone marrow as well. The number of marrow cells per person is taken as 6.7 ~10~~ (12). The best approximation (2) to the data for survivors at Nagasaki is given by the equation I = 4.8x10
-4
+ 807x10
-8 D2
(2)
If we wish the theoretical value of P we have: P=7,2
x
lo-l6 + (2~10~~)~ $&j
D2 e- hi
(3a)
or P=7.2x10-16+2.67x10-18
D2 d- i%i
(3b)
This is to be compared with the experimentally observed value Px = 7.2x10-l6 + 1.3 x 10-l' D2 112
(4)
We can now compare the experimental values at various doses. This is shown in Table I. Table I.
Probability
Dose
(rads)
of Leukemogenesis
for theoretical
per Cell at Different
P
P
Doses
Calc.
0
7.2 xX10-16
7.2 x 10
5
7.5 x lo-l6
7,8 x 10
-15
values
-16 -16 -15
150
3.7 x 10
300
1.2 x lo-l4
1.3 x 10
400
2.1 x lo-l4
8.4 x lo-l5
2.2 x 10
-14
CONCLUSION I have considered a two-hit theory of X or y-ray leukemogenesis in which the first hit inactivates excision repair of base damage and the second hit causes the derepression of the first of a two operator system such that the substance MGI can not be made. This causes the leukemic state in which leukocytes do not mature. The agreement between theory and the observed results from the victims of Nagasaki is good. It may be possible that at high doses of the order of 400 rads, the factor (1 - I) is affected so that-the calculated incidence is higher than expected. REFERENCES 1.
Rosen P. X- or y-ray leukemogenesis cal Biology 75:603, 1979,
2.
Kellerer A M, and Rossi HH. Biophysical aspects of radiation carcinogenesis. P405 in Cancer 1. A comprehensive Treatise, Chemical and Physical Carcinogenesis (F.F, Becker ed.) Plenum Press, Nyew York, (1975).
3.
Abrahamson S, Bender MA, Conger AD, and Wolff S. Uniformity of radiation induced mutation rates among different species. Nature 245: 460, 1973.
4,
Sachs L. Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature 274~535, 1918.
5.
Cerruti P. and Renson JF. Gamma ray excision repair in normal and diseased human cells. P93 in Biology of Radiation Carcinogenesis. (J.M. Yuhas, R.W. Tennant and J,D. Regan eds,) Raven Press, New York 1976.
6.
Corry PM and Cole A. Double strand rejoining Nature 245:100, 1973,
7.
Maniantis F, Efstradiadis A, Sim GK, and Kafatos F. Amplification and characterization of eukaryotic structural genes. P9 in Third Decennial Review Conference: Cell, Tissue and Organ Culture, (Gene Expression and Regulation in Cultured Cells) National Cancer Institute
113
in humans.
Journal of Theoreti-
in mammalian
DNA,
Monograph 48, 1978. 8.
Mattern MR, Hariharan PV, and Cerruti PA. Selective excision of gamma ray damaged thymine from the DNA of cultured mammalian cells. Biochimica et Biophysics Acta 395:48, 1975.
9.
Kourilsky P and Grof F. Genetic control of transcription. Pl9 in Regulation of Gene Expression in Eukaryotic Cells (M. Harris and B. Thompson, eds.) U.S. Government Printing Office: D.H.E.W. Publication NO (NIH) 74-648, 1973.
10.
Mole RH. Ionizing radiation as a carcinogen: practical questions and academic pursuits. British Journal of Radiology 48:157, 1975,
11.
Pitot HC. Fundamentals of Oncology.
12.
Mole RH. Carcinogenesis by ionizing radiation and lessons for other pollutants. P860 in Radiation Research, Proceedings of the Fifth International Congress of Radiation Research. Seattle. (O.F. Nygaard, H,L. Adler and W,K, Sinclair eds.) Academic Press, New York, 1975.
114
Marcel Dekker, New York 1978.