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X- or γ-ray leukemogenesis in humans
J. theor. Biol. (1978) 75, 603-606
X- or y-ray Leukemogenesis in Humans Mole (1975u) has posed the following questions for ionizing radiation induced carcinogenesis or leukemogenesis. Why are probabilites for carcinogenesis or leukemogenesis much smaller than mutation frequencies per locus? Why are probabilities per cell for leukemogenesis for humans lo-l4 at 200 rad? A model for ultraviolet carcinogenesis has been proposed (Rosen, 1975) in which a mutation occurs in the operator region controlling the synthesis of divisional proteins, proteins that are the signals for initiating mitosis (Jones & Donachie, 1973). An extension of this model to ionizing radiation carcinogenesis is now presented. In the ultraviolet case, the damage to the genome responsible for neoplasms has been shown by Setlow & Hart (1975) and by Hart et al. (1977) to be in the form of pyrimidine dimers. For y-rays, we shall assume that the thymine t’ base damage (Cerruti and Remsen 1976) is the major damage causing neoplastic transformation. We wish to point out, however, that Hutchinson (1978) has emphasized that the exact damage causing neoplastic change is not known. Since the only firm numbers for X- or y-ray carcinogenesis in humans are for myeloid leukemia in the Japanese survivors at Nagasaki (Kellerer & Rossi, 1975; Mole, 1975a, 1977), we shall calculate frequencies for myeloid leukemia. It has been pointed out by Metcalf (1971) that leukemia is a disorder of haemopoietic regulation. The first assumption in our model is that there exists a radiation target on the genome which, when struck, initiates events leading to myeloid leukemia. Both chronic and acute myeloid leukemia can be caused by X-irradiation (Miller 1976). The leukemic state corresponds to the presence of immature white cells and not necessarily high white cell counts (Parker 1948). For example, in a typical case of chronic myelogenous leukemia 2% of the white cells are myeloblasts, and in acute myelogenous leukemia 93 % of the white cells are myeloblasts. Fibach et al. (1972) and Sachs (1977) have reported the isolation of a substance, MGI, that can cause immature leukocytes to mature. From this observation, we assume that a repressible gene for the maturation of leukocytes exists. Thus we assume the following scenario: a combination of two repressors (Kourilsky & Gros, 1973) can account for a sequential repres603
0022~5193/78/200603+04 $02,00/O
0 1978 Academic PressInc. (London) Ltd.
604
P.
ROSEN
sion 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 corresponding operator region. If one looks at radiation carcinogenesis or leukemogenesis in humans for y- or X-rays, one sees a dose squared dependence at low dose (Upton, 1961) and (Kellerer & Rossi, 1975). In more recent work Kellerer (1976) indicated that the dose relationship is not definite, and Mole (1977) pointed out the existence of a very small linear coefficient. We shall assume here a dose squared relationship based on a two hit process in which one hit damages a gene specifying a repair process and the second hit causes a carcinogenic or leukemogenic mutation. Cerruti and Remsen have shown that excision repair of t’ damage for example in human cells is excellent. From the mutation frequency per dose per locus data of Abrahamson et al. (1973) for gametes, one can guess estimates for human somatic cells. We assume that the mutation frequency per locus per rad is about 2 x 10m7. It is necessary to estimate here because of the work of Schalet & Sankaranarayanan (1976). We can use this number to make estimates of the probability of a carcinogenesic or leukemogenesic mutation per cell. If the average gene size is L base pairs (B.P.) and the size of a critical operator region is L,, then the probability of carcinogenesis or leukemogenesis per cell in humans will be given by: P = {FD-FD?]
e-DjD37 (1-I)
or p = F2 2 D’. ,-D!Da-r (1 -I), where I is the immunological efficiency, F is the mutation induction frequency per locus (of size L) per rad, and Ds7 is the 37% survival dose of the cells under consideration. For man we will use the average value (I-Z) r l/45 (Rosen, 1976). For leukogenesis we use D 37 s 100 rad for haematopoietic cells (Mole, 1976). Taking L = 1000 B.P. and L,, = 20 B.P., we have calculated the probability of leukemogenesis per cell for four different doses and compared with the data given by Kellerer & Rossi (1975). The results are given in Table 1. The number of marrow cells per person is taken as 6.7 x 101’ (Mole, 1975a). The data of Kellerer & Rossi use Kerma instead of dose (Rossi & Kellerer, 1974), however, at 200 rad the probability is lo-l4 per cell whether one uses dose or Kerma, and the ratio of Kerma to dose is very close to unity. If we use a value of L = 2000 B.P., agreement between observed and calculated values is better. Considering that we are using a simple
LETTERS
TO
THE
TABLE
Probability
of leukemogenesis
Dose
P. Observed
5 200 2.50 400
1
per cell in man at several P Calculated L = 1000
x lo-l6 10-14 1.5 x 10-14 2 x 10-14
x 10-l” 9.4 x 10-14 8.9 x lo-l4 5.1 x 10-14
6.7
605
EDITOR
4.2
doses of X-rays PCalL=2000 2.1 x x x x
4.7 4.5 2.6
10-16 10-14 10-14 lo-l4
exponential inactivation function and that the observed data values have large standard deviation error bars, there certainly is an order of magnitude agreement. Department of Physics and Astronomy University of Massachusetts Amherst, Massachusetts 01003, U.S.A. (Received 31 March
1978,
and in revisedform
PHILIP
ROSEN
23 June 1978)
REFERENCES
ABRAHAMSON, S., BENDER, M. A., CONGER, A. D. & WOLFF, S. (1973). Nature. 245,460. CERRUTI, P. A. & REMSEN,J. F. (1976) In Biology of Radiation Carcinogenesis, (J. M. Yuhas, R. W. Tennant & J. D. Regan, eds) p. 93. New York; Raven Press. FIBACH, E., LANDAU, T., & SACHS, L. (1972). Nature New Biol. 237, 276. HART, R. W., SETLOW, R. B. & WOODHEAD, A. D. (1977). Proc. nat. Acad. Sci. U.S.A. 74, 5574.
HUTCHINSON, F. (1978). Biophys. J. 21, 31a. JONES,N. C. & DONACHIE (1973), Nature 243, 199. KELLERER, A. M. (1976). In Biology of Radiation Carcinogenesis, (J. M. Yuhas, R. W. Tennant & J. D. Regan, eds). p.1. New York: Raven Press. KELLERER, A. M. & ROSSI, H. H. (1975). In Cancer 1. A Comprehensive Treatise, Chemical and Physical Carcinogenesis, (F. F. Becker, ed.) p. 405. New York: Plenum Press. KOURCLSKY,P. & GROS, F. (1973) In Regulation of Gene Expression in Eukaryotic Cells, (M. Harris & B. Thompson, eds). U.S. Government Printing Office: D. H. E. W. Publication No. (NIH) 74-648. METCALF, D. (1971), Med. J. Ausiral. 2, 739. MILLER, R. W. (1976) In Biology of Radiation Carcinogenesis, (J. M. Yuhas, R. W. Tennant & J. D. Regan, eds). p. 45. New York: Raven Press. MOLE, R. H. (1975a) In Radiation Research, Proceedings of the Fifth International Congress of Radiation Research, held at Seattle, Washington, 1974, (0. F. Nygaard, H. I. Adler, & W. K. Sinclair, eds). p. 860. New York: Academic Press. MOLE, R. H. (1975b), Brit. J. of Radial. 48, 157. MOLE, R. H. (1977) In Radiation-Induced Leukemogenesis and Related Viruses, (J. F. Duplan, ed.) p. 19. Amsterdam: North Holland Press. PARKER, E. P. (1948), A Texfbook on Clinical Pathology, pp. 175-181. Baltimore; Williams & Wilkins Co. ROSEN, P. (1975), Int. J. Quant. Chem. IX, 473. ROSEN, P. (1976), Cancer Let. 2, 59.
606
P. ROSEN
ROSSI, H. H. & KELLERER, A. M. (1974), Rad. Res. 58, 131. SACHS, L. (1977) In Cell Differentiation and Neoplasia, 30th Annual Symp. on Fundamental Cancer Research, M. D. Anderson Inst., March 1977, Houston, (G. F. Saunders, ed.) New York : Raven Press. SCHALET, A. P. & SANKARANARAYANAN, K. (1976), Mut. Res. 36, 341. SETLOW, R. B. & HART, R. W. (1975) In Radiation Research, Proceedings of the Fifth International Congress of Radiation Research held at Seattle, Washington 1974, 0. F. Nygaard, H. I. Adler, & W. K. Sinclair, eds). p. 879. New York: Academic Press. UPTON, A. C. (1961), Cam. Res. 21, 717.
X- or y-ray Leukemogenesis in Humans Mole (1975u) has posed the following questions for ionizing radiation induced carcinogenesis or leukemogenesis. Why are probabilites for carcinogenesis or leukemogenesis much smaller than mutation frequencies per locus? Why are probabilities per cell for leukemogenesis for humans lo-l4 at 200 rad? A model for ultraviolet carcinogenesis has been proposed (Rosen, 1975) in which a mutation occurs in the operator region controlling the synthesis of divisional proteins, proteins that are the signals for initiating mitosis (Jones & Donachie, 1973). An extension of this model to ionizing radiation carcinogenesis is now presented. In the ultraviolet case, the damage to the genome responsible for neoplasms has been shown by Setlow & Hart (1975) and by Hart et al. (1977) to be in the form of pyrimidine dimers. For y-rays, we shall assume that the thymine t’ base damage (Cerruti and Remsen 1976) is the major damage causing neoplastic transformation. We wish to point out, however, that Hutchinson (1978) has emphasized that the exact damage causing neoplastic change is not known. Since the only firm numbers for X- or y-ray carcinogenesis in humans are for myeloid leukemia in the Japanese survivors at Nagasaki (Kellerer & Rossi, 1975; Mole, 1975a, 1977), we shall calculate frequencies for myeloid leukemia. It has been pointed out by Metcalf (1971) that leukemia is a disorder of haemopoietic regulation. The first assumption in our model is that there exists a radiation target on the genome which, when struck, initiates events leading to myeloid leukemia. Both chronic and acute myeloid leukemia can be caused by X-irradiation (Miller 1976). The leukemic state corresponds to the presence of immature white cells and not necessarily high white cell counts (Parker 1948). For example, in a typical case of chronic myelogenous leukemia 2% of the white cells are myeloblasts, and in acute myelogenous leukemia 93 % of the white cells are myeloblasts. Fibach et al. (1972) and Sachs (1977) have reported the isolation of a substance, MGI, that can cause immature leukocytes to mature. From this observation, we assume that a repressible gene for the maturation of leukocytes exists. Thus we assume the following scenario: a combination of two repressors (Kourilsky & Gros, 1973) can account for a sequential repres603
0022~5193/78/200603+04 $02,00/O
0 1978 Academic PressInc. (London) Ltd.
604
P.
ROSEN
sion 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 corresponding operator region. If one looks at radiation carcinogenesis or leukemogenesis in humans for y- or X-rays, one sees a dose squared dependence at low dose (Upton, 1961) and (Kellerer & Rossi, 1975). In more recent work Kellerer (1976) indicated that the dose relationship is not definite, and Mole (1977) pointed out the existence of a very small linear coefficient. We shall assume here a dose squared relationship based on a two hit process in which one hit damages a gene specifying a repair process and the second hit causes a carcinogenic or leukemogenic mutation. Cerruti and Remsen have shown that excision repair of t’ damage for example in human cells is excellent. From the mutation frequency per dose per locus data of Abrahamson et al. (1973) for gametes, one can guess estimates for human somatic cells. We assume that the mutation frequency per locus per rad is about 2 x 10m7. It is necessary to estimate here because of the work of Schalet & Sankaranarayanan (1976). We can use this number to make estimates of the probability of a carcinogenesic or leukemogenesic mutation per cell. If the average gene size is L base pairs (B.P.) and the size of a critical operator region is L,, then the probability of carcinogenesis or leukemogenesis per cell in humans will be given by: P = {FD-FD?]
e-DjD37 (1-I)
or p = F2 2 D’. ,-D!Da-r (1 -I), where I is the immunological efficiency, F is the mutation induction frequency per locus (of size L) per rad, and Ds7 is the 37% survival dose of the cells under consideration. For man we will use the average value (I-Z) r l/45 (Rosen, 1976). For leukogenesis we use D 37 s 100 rad for haematopoietic cells (Mole, 1976). Taking L = 1000 B.P. and L,, = 20 B.P., we have calculated the probability of leukemogenesis per cell for four different doses and compared with the data given by Kellerer & Rossi (1975). The results are given in Table 1. The number of marrow cells per person is taken as 6.7 x 101’ (Mole, 1975a). The data of Kellerer & Rossi use Kerma instead of dose (Rossi & Kellerer, 1974), however, at 200 rad the probability is lo-l4 per cell whether one uses dose or Kerma, and the ratio of Kerma to dose is very close to unity. If we use a value of L = 2000 B.P., agreement between observed and calculated values is better. Considering that we are using a simple
LETTERS
TO
THE
TABLE
Probability
of leukemogenesis
Dose
P. Observed
5 200 2.50 400
1
per cell in man at several P Calculated L = 1000
x lo-l6 10-14 1.5 x 10-14 2 x 10-14
x 10-l” 9.4 x 10-14 8.9 x lo-l4 5.1 x 10-14
6.7
605
EDITOR
4.2
doses of X-rays PCalL=2000 2.1 x x x x
4.7 4.5 2.6
10-16 10-14 10-14 lo-l4
exponential inactivation function and that the observed data values have large standard deviation error bars, there certainly is an order of magnitude agreement. Department of Physics and Astronomy University of Massachusetts Amherst, Massachusetts 01003, U.S.A. (Received 31 March
1978,
and in revisedform
PHILIP
ROSEN
23 June 1978)
REFERENCES
ABRAHAMSON, S., BENDER, M. A., CONGER, A. D. & WOLFF, S. (1973). Nature. 245,460. CERRUTI, P. A. & REMSEN,J. F. (1976) In Biology of Radiation Carcinogenesis, (J. M. Yuhas, R. W. Tennant & J. D. Regan, eds) p. 93. New York; Raven Press. FIBACH, E., LANDAU, T., & SACHS, L. (1972). Nature New Biol. 237, 276. HART, R. W., SETLOW, R. B. & WOODHEAD, A. D. (1977). Proc. nat. Acad. Sci. U.S.A. 74, 5574.
HUTCHINSON, F. (1978). Biophys. J. 21, 31a. JONES,N. C. & DONACHIE (1973), Nature 243, 199. KELLERER, A. M. (1976). In Biology of Radiation Carcinogenesis, (J. M. Yuhas, R. W. Tennant & J. D. Regan, eds). p.1. New York: Raven Press. KELLERER, A. M. & ROSSI, H. H. (1975). In Cancer 1. A Comprehensive Treatise, Chemical and Physical Carcinogenesis, (F. F. Becker, ed.) p. 405. New York: Plenum Press. KOURCLSKY,P. & GROS, F. (1973) In Regulation of Gene Expression in Eukaryotic Cells, (M. Harris & B. Thompson, eds). U.S. Government Printing Office: D. H. E. W. Publication No. (NIH) 74-648. METCALF, D. (1971), Med. J. Ausiral. 2, 739. MILLER, R. W. (1976) In Biology of Radiation Carcinogenesis, (J. M. Yuhas, R. W. Tennant & J. D. Regan, eds). p. 45. New York: Raven Press. MOLE, R. H. (1975a) In Radiation Research, Proceedings of the Fifth International Congress of Radiation Research, held at Seattle, Washington, 1974, (0. F. Nygaard, H. I. Adler, & W. K. Sinclair, eds). p. 860. New York: Academic Press. MOLE, R. H. (1975b), Brit. J. of Radial. 48, 157. MOLE, R. H. (1977) In Radiation-Induced Leukemogenesis and Related Viruses, (J. F. Duplan, ed.) p. 19. Amsterdam: North Holland Press. PARKER, E. P. (1948), A Texfbook on Clinical Pathology, pp. 175-181. Baltimore; Williams & Wilkins Co. ROSEN, P. (1975), Int. J. Quant. Chem. IX, 473. ROSEN, P. (1976), Cancer Let. 2, 59.
606
P. ROSEN
ROSSI, H. H. & KELLERER, A. M. (1974), Rad. Res. 58, 131. SACHS, L. (1977) In Cell Differentiation and Neoplasia, 30th Annual Symp. on Fundamental Cancer Research, M. D. Anderson Inst., March 1977, Houston, (G. F. Saunders, ed.) New York : Raven Press. SCHALET, A. P. & SANKARANARAYANAN, K. (1976), Mut. Res. 36, 341. SETLOW, R. B. & HART, R. W. (1975) In Radiation Research, Proceedings of the Fifth International Congress of Radiation Research held at Seattle, Washington 1974, 0. F. Nygaard, H. I. Adler, & W. K. Sinclair, eds). p. 879. New York: Academic Press. UPTON, A. C. (1961), Cam. Res. 21, 717.