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The use of antithyroid therapy in the treatment of neoplastic conditions with cytotoxic drugs
Medical THE
Hypotheses USE
OF
ANTITHYROID
WITH
CYTOTOXIC
V.M.
Dixit
University
5:
and of
1333-1336, THERAPY
1979 IN
THE
TREATMENT
OF
NEOPLASTIC
CONDITIONS
DRUGS E.S.G. Nairobi,
, Dept.
Hettiaratch PO
Box
30197,
Nairobi,
of
Medical
Physiology,
Kenya.
ABSTRACT Taking into account the known actions of thyroid hormone, we suggest that standard antithyroid therapy may be used to create a situation of greater sensitivity to cytotoxic drugs in tumour tissues as compared with normal tissues.
INTRODUCTION Different means have been tried to increase the sensitivity of tumour tissue to irradiation as compared to normal tissues which are inevitably exposed during irradiation. A similar means of creating a differential sensitivity between tumour and normal tissues to cytotoxic agents would be an useful adjunct to cytotoxic therapy. We suggest that such a difference in sensitivity may be produced by antithyroid therapy prior to the administration of the cytotoxic agents. This hypothesis is based on the known actions of thyroid hormone and factors known to contra cell division. Actions of Thyroid Hormone (TH) The classical concept of the action of TH was that it uncouples oxidative energy release from phosphorylation in the mitochondria (1,x,3). This fails to explain the role of TH in growth and maturation and is almost certainly an effect of unphysiological concentration of the hormone. Other actions of TH occurring at more physiological concentrations have been elucidated recently. TH has been shown to stimulate protein synthesis. This seems to be brought about either by the promotion of transcription of DNA or by the facilitation of the transfer of RNA across the nuclear membrane, and probably by facilitation of the subsequent translation nrocess as well (4,5). These actions are likely to be the result of binding of TH to nuclear chromation (6). TH also seems to stimulate the entry of amino acids into cells by an action on the cell membrane (7). Unlike the uncoupling action of large concentrations of TH, more physiological concentrations appear to increase the generation of ATP. Thus Bronk has shown that the oxidative capacity of the rat mitochondria is markedly reduced by thyroidectomy and restored by the injection of triiodothyronine (8,9). There is also evidence that the ADP uptake of
1333
mitochondria is increased by triiodothyronine (lO,ll), and that vesicles prepared from mitochondria are stimulated to generate ATP when TH is added in very low concentrations (12). A specific mitochondrial action of the hormone is strongly supported by the finding of specific high affinity thyroxine binding receptors on the inner membrane of mitochondria
(13).
TH has also been shown to increase the activity of the plasma membrane sodium pump by increasing the number of pump units per unit area of the membrane rather than by increasing the activity of pre-existing sodium pump units (14,15). Since sodium pump activity is associated with the enzyme Na-K adenosine triphosphatase (16), this is probably an effect of TH on protein synthesis. This action on the sodium pumps seems to be permissive rather than absolute since it only increases the activity of the pump above a certain basal level. It has been estimated that as much as 40% of the energy expenditure of the cell is used to maintain sodium pump activity. Factors controlling cell division Protein synthesis is an essential requirement for cell division. The mitotic rate is also influenced by the energy status of the cell wfiich is most conveniently defined by its energy charge (18). Thus, Guttes and Guttes (19) have demonstrated that when the unicellular ciliate cell of Stentor coeruleus is bisected so that nuclear components are equally distributed in the two halves, cell division is slower in the half containing the energy consuming ciliary apparatus than in the other, Epel aleo finds that mitosis stops when the ATP level falls below a critical value (20). Mitosis in the dermis of man is maximam during sleep falling markedly during the day when the energy charge is lowest and becoming almost completely inhibited by exercise (2). All these lines of evidence suggest that the rate of mitosis of normal cells is directly related to their energy charge. CONCLUSION The hypothyroid state produced by antithyroid drugs can therefore be expected to be characterised by a decrease in the energy charge of tissue cells as a consequence of a decrease in the rate of generation of ATP in the face of a cont+nuing, though reduced, rate of dissipation of energy mainly for maintaining sodium pump activity. The hypothyroid state would also engender a reduced rate of protein synthesis by cells. As a result of both these actions the rate of mitosis of normal cells would decrease. However, tumour cells are unlikely to be affected in this way by the hypothyroid state as these cells are usually autonomous. Since the sensitivity of cells to cytotoxic agents is a function of their mitotic rate, it is proposed that a period of antithyroid therapy prior to the exhibitinn of cytotoxic drugs would have the effect of protecting normal tissues from the effects of ruch drugs. This protective effect would be particularly marked in tissues such as the bone marrow where cell
1334
division rates are high. The dosage and duration of therapy with cytotoxic drugs are often limited by their bone marrow depressing effect; and an induction of a hypothyroid state before such therapy should enable the cytotoxic agent to be used in higher dosage and for a longer time without ill effects on normal tissues.
REFERENCES 1.
Martius, C, Hess B. Mode of action of thyroxine. Arch. Biochem. Biophys. 33: 486, 1951.
2.
Hoch FL, Jinmann F. by thyroid hormone.
13 . .
Tapley DF, Cooper C, Lehninger AL. The action of thyroxine on mitochondria and oxidative phosphorylation. Biochem, Biophys. Acta 18: 597, 1955.
4.
Tata JR, Ernster I, Lindberg 0. The action of thyroid hormone at cell level. Biochem. J. 86: 108, 1963.
5.
Tata JR. Growth and developmental action of thyroid hormone at cellular level. p 469 in Handbook of Physiology Section 7 Volume 3 (Roy 0 Greep, E.B. Astwood eds) American Physiological Society, Washington, 1974.
6.
De Groot LJ, Torresani, J. Triiodothyronine binding to isolated liver cell nucleii. Endocrinology. 93: 357, 1975.
7.
Adamson, CF, Ingbar SH. Selective alteration by triiodothyronine of amino acid transport in embryonic bone. Endocrinology 81: 1362, 1967.
8.
Bronk JR, Bronk MS. The influence of thyroxine on oxidative phosphorylation in mitochondria from thyroidectomised rats. J. Biol. Chem. 237: 897. 1962.
9.
Bronk JR. Thyroid hormone effects on eiectron transport. Science 153: 638, 1966.
10
Babior BM, Creagan S. Ingbar SH et al. Stimulation of mitochondrial ADP uptake by thyroid hormone. Proc. Natl. Acad. Sci. U.S.A. 70: 98, 1973.
11
Postnay GI, MacClendon FD, Bush JE, et al. The effect of physiological doses of thyroxine on carrier mediated ADP uptake by liver mitochondria from thyroidectomised rats. Biochem. Biophys. Res. Communication 55:17: 1973.
12.
Sterling K. Milch PO, Brenner MA, et al. Thyroid hormone action, the mitochondrial pathway. S,cience 197: 996, 1977.
The uncoupling of respiration and phosohorylation Proc. Natl. Acad. Sci. U.S.A. 40: 909, 1954.
1335
13.
Sterling, K. Lazarus JH, Milch PO, et al. Mitochondrial thyroid hormone receptors, localisation and physiological significance. Science 201: 1126, 1978.
14.
Ismail-Beigi F, Edelman IS. The mechanism of the calorigenic action of thyroid hormone, stimulation of Na-K activated adenosine triphosphatase activity. J. Gen. Physiol. 57:710, 1971.
15.
Lo CS, Edelman IS. Effect of triiodothyronineon the synthesis and degradation of renal cortial Na-K adenosine triphosphatase. J. Biol. Chem. 251: 7834, 1976.
16.
Skou JC. Enzymatic basis for active transport of Na+ and K' across cell membranes. Physiological Reviews 45: 596, 1965.
17.
Blanchard RF, Davis PJ. Dependance of renal Na-K adenosine triphosphatase on subphysiologic levels of thyroid hormone in vitro. Presented at the 54th meeting of the American Thyroid Society, Portland, Oregon, Sept. 13-16, 1978 and quoted by Sterling K. 11~Thyroid hormone action at cell level. New England Journal of Medicine 300: 1483 (1959).
18.
Atkinson DE. Energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers. Biochemistry 7: 4030, 1968.
19.
Guttes E, Guttes S. Regulation of mitosis in Stentor coeruleus. Science 129: 1483, (1959).
20.
Epel E. The effects of carbon monoxide inhibition on ATP level and the rate of mitosis in the sea urchin egg. J. Cell Biology 17: 315, 1963.
21.
Fisher LB. Diurnal mitotic rhythm in the human epidermis. British Journal of Dermatology 80: 75, 1968.
1336
Hypotheses USE
OF
ANTITHYROID
WITH
CYTOTOXIC
V.M.
Dixit
University
5:
and of
1333-1336, THERAPY
1979 IN
THE
TREATMENT
OF
NEOPLASTIC
CONDITIONS
DRUGS E.S.G. Nairobi,
, Dept.
Hettiaratch PO
Box
30197,
Nairobi,
of
Medical
Physiology,
Kenya.
ABSTRACT Taking into account the known actions of thyroid hormone, we suggest that standard antithyroid therapy may be used to create a situation of greater sensitivity to cytotoxic drugs in tumour tissues as compared with normal tissues.
INTRODUCTION Different means have been tried to increase the sensitivity of tumour tissue to irradiation as compared to normal tissues which are inevitably exposed during irradiation. A similar means of creating a differential sensitivity between tumour and normal tissues to cytotoxic agents would be an useful adjunct to cytotoxic therapy. We suggest that such a difference in sensitivity may be produced by antithyroid therapy prior to the administration of the cytotoxic agents. This hypothesis is based on the known actions of thyroid hormone and factors known to contra cell division. Actions of Thyroid Hormone (TH) The classical concept of the action of TH was that it uncouples oxidative energy release from phosphorylation in the mitochondria (1,x,3). This fails to explain the role of TH in growth and maturation and is almost certainly an effect of unphysiological concentration of the hormone. Other actions of TH occurring at more physiological concentrations have been elucidated recently. TH has been shown to stimulate protein synthesis. This seems to be brought about either by the promotion of transcription of DNA or by the facilitation of the transfer of RNA across the nuclear membrane, and probably by facilitation of the subsequent translation nrocess as well (4,5). These actions are likely to be the result of binding of TH to nuclear chromation (6). TH also seems to stimulate the entry of amino acids into cells by an action on the cell membrane (7). Unlike the uncoupling action of large concentrations of TH, more physiological concentrations appear to increase the generation of ATP. Thus Bronk has shown that the oxidative capacity of the rat mitochondria is markedly reduced by thyroidectomy and restored by the injection of triiodothyronine (8,9). There is also evidence that the ADP uptake of
1333
mitochondria is increased by triiodothyronine (lO,ll), and that vesicles prepared from mitochondria are stimulated to generate ATP when TH is added in very low concentrations (12). A specific mitochondrial action of the hormone is strongly supported by the finding of specific high affinity thyroxine binding receptors on the inner membrane of mitochondria
(13).
TH has also been shown to increase the activity of the plasma membrane sodium pump by increasing the number of pump units per unit area of the membrane rather than by increasing the activity of pre-existing sodium pump units (14,15). Since sodium pump activity is associated with the enzyme Na-K adenosine triphosphatase (16), this is probably an effect of TH on protein synthesis. This action on the sodium pumps seems to be permissive rather than absolute since it only increases the activity of the pump above a certain basal level. It has been estimated that as much as 40% of the energy expenditure of the cell is used to maintain sodium pump activity. Factors controlling cell division Protein synthesis is an essential requirement for cell division. The mitotic rate is also influenced by the energy status of the cell wfiich is most conveniently defined by its energy charge (18). Thus, Guttes and Guttes (19) have demonstrated that when the unicellular ciliate cell of Stentor coeruleus is bisected so that nuclear components are equally distributed in the two halves, cell division is slower in the half containing the energy consuming ciliary apparatus than in the other, Epel aleo finds that mitosis stops when the ATP level falls below a critical value (20). Mitosis in the dermis of man is maximam during sleep falling markedly during the day when the energy charge is lowest and becoming almost completely inhibited by exercise (2). All these lines of evidence suggest that the rate of mitosis of normal cells is directly related to their energy charge. CONCLUSION The hypothyroid state produced by antithyroid drugs can therefore be expected to be characterised by a decrease in the energy charge of tissue cells as a consequence of a decrease in the rate of generation of ATP in the face of a cont+nuing, though reduced, rate of dissipation of energy mainly for maintaining sodium pump activity. The hypothyroid state would also engender a reduced rate of protein synthesis by cells. As a result of both these actions the rate of mitosis of normal cells would decrease. However, tumour cells are unlikely to be affected in this way by the hypothyroid state as these cells are usually autonomous. Since the sensitivity of cells to cytotoxic agents is a function of their mitotic rate, it is proposed that a period of antithyroid therapy prior to the exhibitinn of cytotoxic drugs would have the effect of protecting normal tissues from the effects of ruch drugs. This protective effect would be particularly marked in tissues such as the bone marrow where cell
1334
division rates are high. The dosage and duration of therapy with cytotoxic drugs are often limited by their bone marrow depressing effect; and an induction of a hypothyroid state before such therapy should enable the cytotoxic agent to be used in higher dosage and for a longer time without ill effects on normal tissues.
REFERENCES 1.
Martius, C, Hess B. Mode of action of thyroxine. Arch. Biochem. Biophys. 33: 486, 1951.
2.
Hoch FL, Jinmann F. by thyroid hormone.
13 . .
Tapley DF, Cooper C, Lehninger AL. The action of thyroxine on mitochondria and oxidative phosphorylation. Biochem, Biophys. Acta 18: 597, 1955.
4.
Tata JR, Ernster I, Lindberg 0. The action of thyroid hormone at cell level. Biochem. J. 86: 108, 1963.
5.
Tata JR. Growth and developmental action of thyroid hormone at cellular level. p 469 in Handbook of Physiology Section 7 Volume 3 (Roy 0 Greep, E.B. Astwood eds) American Physiological Society, Washington, 1974.
6.
De Groot LJ, Torresani, J. Triiodothyronine binding to isolated liver cell nucleii. Endocrinology. 93: 357, 1975.
7.
Adamson, CF, Ingbar SH. Selective alteration by triiodothyronine of amino acid transport in embryonic bone. Endocrinology 81: 1362, 1967.
8.
Bronk JR, Bronk MS. The influence of thyroxine on oxidative phosphorylation in mitochondria from thyroidectomised rats. J. Biol. Chem. 237: 897. 1962.
9.
Bronk JR. Thyroid hormone effects on eiectron transport. Science 153: 638, 1966.
10
Babior BM, Creagan S. Ingbar SH et al. Stimulation of mitochondrial ADP uptake by thyroid hormone. Proc. Natl. Acad. Sci. U.S.A. 70: 98, 1973.
11
Postnay GI, MacClendon FD, Bush JE, et al. The effect of physiological doses of thyroxine on carrier mediated ADP uptake by liver mitochondria from thyroidectomised rats. Biochem. Biophys. Res. Communication 55:17: 1973.
12.
Sterling K. Milch PO, Brenner MA, et al. Thyroid hormone action, the mitochondrial pathway. S,cience 197: 996, 1977.
The uncoupling of respiration and phosohorylation Proc. Natl. Acad. Sci. U.S.A. 40: 909, 1954.
1335
13.
Sterling, K. Lazarus JH, Milch PO, et al. Mitochondrial thyroid hormone receptors, localisation and physiological significance. Science 201: 1126, 1978.
14.
Ismail-Beigi F, Edelman IS. The mechanism of the calorigenic action of thyroid hormone, stimulation of Na-K activated adenosine triphosphatase activity. J. Gen. Physiol. 57:710, 1971.
15.
Lo CS, Edelman IS. Effect of triiodothyronineon the synthesis and degradation of renal cortial Na-K adenosine triphosphatase. J. Biol. Chem. 251: 7834, 1976.
16.
Skou JC. Enzymatic basis for active transport of Na+ and K' across cell membranes. Physiological Reviews 45: 596, 1965.
17.
Blanchard RF, Davis PJ. Dependance of renal Na-K adenosine triphosphatase on subphysiologic levels of thyroid hormone in vitro. Presented at the 54th meeting of the American Thyroid Society, Portland, Oregon, Sept. 13-16, 1978 and quoted by Sterling K. 11~Thyroid hormone action at cell level. New England Journal of Medicine 300: 1483 (1959).
18.
Atkinson DE. Energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers. Biochemistry 7: 4030, 1968.
19.
Guttes E, Guttes S. Regulation of mitosis in Stentor coeruleus. Science 129: 1483, (1959).
20.
Epel E. The effects of carbon monoxide inhibition on ATP level and the rate of mitosis in the sea urchin egg. J. Cell Biology 17: 315, 1963.
21.
Fisher LB. Diurnal mitotic rhythm in the human epidermis. British Journal of Dermatology 80: 75, 1968.
1336