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Adriamycin and cardiac toxicity
Volume 89 Number 3
L e t t e r s to the E d i t o r
Nerve-growth factor and neuroblastoma To the'Editor: The recent paper by Weetman and associates' prompts me to comment on the possible role of nerve-growth factor (NGF) in neuroblastoma. In light of the known effects of nerve-growth factor (a protein capable of inducing differentiation and maintaining the life of sympathetic cells) ~ on neuroblastoma cells~ and the known biochemical effects of nerve-growth factor, *, ~one could postulate an explanation which may help account, in part, not only for the high urinary vanillylmandelic acid ~ dopamine, '~norepinephrine, ~ and epinephrine ~ levels in children with neuroblastoma (NB), 7 b u t also for the demise of the immunologic response in some patients with NB? -~1 Revoltella and associates a have shown that murine NB and normal sympathetic cells bind NGF in vitro on their membrane surface. More specifically, they have demonstrated ~ that this binding of ['2~I] NGF, which appears to be maximal during the Gi and early S phase, is not mediated by divalent cations and is not dependent on cell metabolic activity. The binding capacity exhibited at saturation by NB cells or sympathetic murine cells was 40 to 70 times higher than that shown by an equal number of other tumor or normal cells? Also, the receptor for N G F binding is most likely of a protein nature and specific for NGF.:' Hendry and Thoenen, ' after the removal of the submaxillary glands (one of the apparent sites o f NGF synthesis in adult mice), have demonstrated a decrease, at the level of the superior cervical and stellate ganglia, in the activity of tyrosine hydroxylase (TH) and dopamine fi-hydroxylase (DBH), the key enzymes in the synthesis of the adrenergic transmitter, norepinephrine (NE). Thus, a decrease in NE synthesis and sympathetic nervous system activity would result. It would then seem logical to postulate that elevated NGF levels in the blood, sympathetic ganglia, and/or NB tumor mass could result in a commensurate increase in TH and DBH activity with a concomitant elevation of dopamine, NE, and epinephrine levels in the blood, sympathetic ganglia, and/or NB tumor mass with a possible net catabolic effect. Anabolic effects of N G F must also be considered in light of its proinsulin-like structure ~ and demonstrated ability to increase the total protein content of the superior sympathetic ganglia. * Thus, in those patients with neuroblastoma, the assumed, resultant plasma dopamine, NE, and epinephrine increases could, (1) play a role in accounting for the elevated urinary vanillylmandelic acid, dopamine, NE, and epinephrine levels. (2) Because epinephrine has been shown to elevate leukocyte cyclic AMP levels? reduce production or secretion of antibody, ~ suppress T-cell mediated cytolysis,'" and reduce DNA synthesis in both T and B lymphocytes after mitogen stimulation, '~ the assumed, resultant elevated plasma epinephrine levels could serve, in part, to compromise the immunologic status of patients
with neuroblastoma. In conclusion, in patients with neuroblastoma, higher NGF levels might be correlated with proportional increases in urinary
5 17
catecholamine levels which, in turn, might be correlated with a less competent immunologic defense mechanism and a poorer prognosis. Albert F. DiNicola Medical student 58 Union St. Brighton, Mass. 02135 REFERENCES 1. Weetman RM, Rider PS, Oei TO, Hempel JS, and Baehner RL: Effect of diet on urinary excretion of VMA, HVA, metanephrine, and total free catecholamine in normal preschool children, J P~DIATR 88:46, 1976. 2. Levi-Montalcini R, and Angeletti PU: Nerve growth factor, Physiol Rev 48:534, 1968. 3. Revoltella R, Bertolini L, Pediconi M, et al: Specific binding of nerve growth factor by murine C 1300 neuroblastoma cells, J Exp Med 140:437, 1974. 4. Hendry IA, and Thoenen H: Changes of enzyme pattern in the sympathetic nervous system of adult mice after submaxillary gland removal: response to exogenous nerve growth factor, J Neurochem 22:999, 1974. 5. Bradshaw RA, Hogue-Angeletti RA, and Frazier WA: Nerve growth factor and insulin: evidence of similarities in structure, function and mechanism of action, Recent Prog Horm Res 30:575, 1974. 6. Martin LW, and Kosloske AM: Heel cord shortening with ganglioneuroblastoma, Am J Dis Child 129:254, 1975. 7. Gitlow SE, Bertani LM, Rausen A, et al: Diagnosis of neuroblastoma by qualitative and quantitative determination of catecholamine metabolites in urine, Cancer 25:1377, 1970. 8. Bourne HR, Lichtenstein LM, Melmon KL, et al: Modulation of inflammation and immunity by cyclic AMP, Science 184:19, 1974. 9. Melmon KL, Bourne HR, Weinstein Y, et al: Hemolytic plaque formation by leukocytes in vitro, J Clin Invest 53:13, 1974. 10. Henney CS, and Lichenstein LM: Role of cyclic AMP in the cytolytic activity of lymphocytes, J Immunol 107:610, 1971. 11. Diamantstein T, and Ulmer A: The antagonistic action of cyclic GMP and cyclic AMP on proliferation of B and T lymphocytes, Immunology 28:113, 1975.
Adriamycin and cardiac toxicity To the Editor: In their article, "Adriamycin cardiotoxicity in a child with Wilms tumor," Dr. Gerber and associates ~ presented a case of cardiomyopathy at a level (350 m g / m ~) below the recommended safe norm for the drug (500 mg/m~-). Their patient had received previous irradiation. Irradiation and concurrent cyclophosphamide therapy have been associated with Adriamyein cardiomyopathy at levels below the suggested value and might account for their observation. ~ We have recently had experience with a three-year-old boy
5 18
Letters to the Editor
with acute leukemia who developed signs of cardiomyopathy at a "low" dose of Adriamycin. In contrast, this patient had not received irradiation nor cyclophosphamide. During his sevenmonth course, Patient T. B. received a total dose of 135 mg (270 mg/m=') of Adriamycin and 60 mg (120 m g / m ~) of Daunomycin. This is a total cumulative dose of 390 m g / m ~. Adriamycin is a closely related analog of Daunomycin with similar pharmokinetics. There is evidence that the toxicity results for aglycones of both. 3 The clinical course, cardiotoxicity, pathology, and electron microscopy are identical for both medications. We consider these drugs as having cumulative effects and would utilize the same maximum dose (500 mg/m'-') as if used singly. We would like to re-emphasize Dr. Gerber's conclusion. "The assumption that a total dose of Adriamycin less than 500 m g / m ~ is safe in terms of cardiac toxicity may n o t be valid." It is important to emphasize this restricting aspect of Adriamycin therapy. Unfortunately, there is no clearcut e,arly indication of incipient cardiomyopathy. The electrocardiogram, roentgenogram, echocardiogram, and physical examination demonstrated the signs and symptoms of cardiomyopathy and at present there are no reproducible early clues of developing cardiac dysfunction. Robert P. Rieker, M.D. Assistant Professor of Pediatrics Richard B. Patterson, M.D. Professor of Pediatrics Bowman Gray School of Medicine Winston-Salem, N.C. 27103 REFERENCES
1.
2.
3.
Gerber MA, Gilbert EM, and Chung K J: Adriamycin cardiotoxicity in a child with Wilms tumor, J P:nDiArn 87:629, 1975. Gilladoga AC, Manuel C, Tan CC, Wollner N, and Murphy ML: Cardiotoxicity o f Adriamycin (NSC-123127) in children, Cancer Chemother Rep Part 3, 6:209, 1975. Herman E, Mhatre R, Lee IP, Vick J, and Waravdekar VS: A comparison of the cardiovascular actions of Daunomycin, Adriamycin and N-Acetyldaunomycin in hamsters and monkeys, Pharmacology 6:230, 1971.
Electroencephalogram in hypothyroidism in the neonate To the Editor: We read with interest the article entitled "Congenital hypothyroidism-signs and symptoms in the newborn period," by Smith and associates' which appeared in the December issue of TI~E JOURNAL. We have recently encountered two patients with congenital hypothyroidism and noted two other abnormalities which add to the spectrum of the disease. Initial electroencephalographic examination revealed generalized slowing of wave activity. Ten days after replacement thyroid therapy, there was a definite increase in theta and delta activity.
The Journal of Pediatrics September 1976
As thyroid hormone studies became normal, the electroencephalogram reverted to a normal pattern. Electrocardiographic monitoring showed large, "domeshaped" T waves in lead II, the so-called "Mosque sign. TM This abnormality reverted to normal during the second week of replacement therapy. Steven C. Shapiro, M.D. Gilbert L Martin, M.D. Magan Medical Clinic, Inc. 420 West Rowland St. Covina, Calif. 91723 REFERENCES
1.
2.
Smith DW, Klein AM, Henderson JR, and Myrianthopoulos NC: Congenital hypothyroidism signs and symptoms in the newborn period, J PEDIATR 87:958, 1975. Ertugrul A: A new electrocardiographic observation in infants and children with hypothyroidism, Pediatrics 37:669, 1966.
Host inhibitory or blocking factor in subacute sclerosing panencephalitis To the Editor: The article by Steele and co-workers' expands the increasing body of evidence that an altered cellular immune response is important in the pathogenesis of subacute sclerosing panencephalitis (SSPE). Although children with this disease may not have a basic immune defect, the evidence presented in this article and others ~ has led to the conclusion that an effective host response to the SSPE virus is somehow prevented. We have recdhtly reported :' a heat-stable blocking factor in the plasma of eight patients with SSPE tha~ interfered with lymphocyte reactivity to phytohemagglutinin and in mixed lymphocyte cultures, in vitro assays of immune function. The amount of blocking factor increased with increasing activity or duration of disease; patients with more advanced disease had greater degrees of blocking. Steele and associates state that a blocking factor is "not universally demonstrable" in SSPE patients. Perhaps this is due to the fact that some patients have been studied during the early stages o f disease. Steele does not comment upon the stage of disease when their patients were studied or when the blocking factor was demonstrated. The blocking factor has not yet been completely characterized, but as suggested, a high-molecular weight immunoglobulin or an antigen-antibody complex seem the most likely possibilities. Continuing work in our laboratory suggests that the blocking factor might be an antigen-antibody complex involving theta antigen. Whatever the nature of the blocking factor, we would agree with Steele and associates that such a compound probably contributes to the pathogenesis of SSPE by preventing an effective host response to the SSPE virus. Therefore, specific
L e t t e r s to the E d i t o r
Nerve-growth factor and neuroblastoma To the'Editor: The recent paper by Weetman and associates' prompts me to comment on the possible role of nerve-growth factor (NGF) in neuroblastoma. In light of the known effects of nerve-growth factor (a protein capable of inducing differentiation and maintaining the life of sympathetic cells) ~ on neuroblastoma cells~ and the known biochemical effects of nerve-growth factor, *, ~one could postulate an explanation which may help account, in part, not only for the high urinary vanillylmandelic acid ~ dopamine, '~norepinephrine, ~ and epinephrine ~ levels in children with neuroblastoma (NB), 7 b u t also for the demise of the immunologic response in some patients with NB? -~1 Revoltella and associates a have shown that murine NB and normal sympathetic cells bind NGF in vitro on their membrane surface. More specifically, they have demonstrated ~ that this binding of ['2~I] NGF, which appears to be maximal during the Gi and early S phase, is not mediated by divalent cations and is not dependent on cell metabolic activity. The binding capacity exhibited at saturation by NB cells or sympathetic murine cells was 40 to 70 times higher than that shown by an equal number of other tumor or normal cells? Also, the receptor for N G F binding is most likely of a protein nature and specific for NGF.:' Hendry and Thoenen, ' after the removal of the submaxillary glands (one of the apparent sites o f NGF synthesis in adult mice), have demonstrated a decrease, at the level of the superior cervical and stellate ganglia, in the activity of tyrosine hydroxylase (TH) and dopamine fi-hydroxylase (DBH), the key enzymes in the synthesis of the adrenergic transmitter, norepinephrine (NE). Thus, a decrease in NE synthesis and sympathetic nervous system activity would result. It would then seem logical to postulate that elevated NGF levels in the blood, sympathetic ganglia, and/or NB tumor mass could result in a commensurate increase in TH and DBH activity with a concomitant elevation of dopamine, NE, and epinephrine levels in the blood, sympathetic ganglia, and/or NB tumor mass with a possible net catabolic effect. Anabolic effects of N G F must also be considered in light of its proinsulin-like structure ~ and demonstrated ability to increase the total protein content of the superior sympathetic ganglia. * Thus, in those patients with neuroblastoma, the assumed, resultant plasma dopamine, NE, and epinephrine increases could, (1) play a role in accounting for the elevated urinary vanillylmandelic acid, dopamine, NE, and epinephrine levels. (2) Because epinephrine has been shown to elevate leukocyte cyclic AMP levels? reduce production or secretion of antibody, ~ suppress T-cell mediated cytolysis,'" and reduce DNA synthesis in both T and B lymphocytes after mitogen stimulation, '~ the assumed, resultant elevated plasma epinephrine levels could serve, in part, to compromise the immunologic status of patients
with neuroblastoma. In conclusion, in patients with neuroblastoma, higher NGF levels might be correlated with proportional increases in urinary
5 17
catecholamine levels which, in turn, might be correlated with a less competent immunologic defense mechanism and a poorer prognosis. Albert F. DiNicola Medical student 58 Union St. Brighton, Mass. 02135 REFERENCES 1. Weetman RM, Rider PS, Oei TO, Hempel JS, and Baehner RL: Effect of diet on urinary excretion of VMA, HVA, metanephrine, and total free catecholamine in normal preschool children, J P~DIATR 88:46, 1976. 2. Levi-Montalcini R, and Angeletti PU: Nerve growth factor, Physiol Rev 48:534, 1968. 3. Revoltella R, Bertolini L, Pediconi M, et al: Specific binding of nerve growth factor by murine C 1300 neuroblastoma cells, J Exp Med 140:437, 1974. 4. Hendry IA, and Thoenen H: Changes of enzyme pattern in the sympathetic nervous system of adult mice after submaxillary gland removal: response to exogenous nerve growth factor, J Neurochem 22:999, 1974. 5. Bradshaw RA, Hogue-Angeletti RA, and Frazier WA: Nerve growth factor and insulin: evidence of similarities in structure, function and mechanism of action, Recent Prog Horm Res 30:575, 1974. 6. Martin LW, and Kosloske AM: Heel cord shortening with ganglioneuroblastoma, Am J Dis Child 129:254, 1975. 7. Gitlow SE, Bertani LM, Rausen A, et al: Diagnosis of neuroblastoma by qualitative and quantitative determination of catecholamine metabolites in urine, Cancer 25:1377, 1970. 8. Bourne HR, Lichtenstein LM, Melmon KL, et al: Modulation of inflammation and immunity by cyclic AMP, Science 184:19, 1974. 9. Melmon KL, Bourne HR, Weinstein Y, et al: Hemolytic plaque formation by leukocytes in vitro, J Clin Invest 53:13, 1974. 10. Henney CS, and Lichenstein LM: Role of cyclic AMP in the cytolytic activity of lymphocytes, J Immunol 107:610, 1971. 11. Diamantstein T, and Ulmer A: The antagonistic action of cyclic GMP and cyclic AMP on proliferation of B and T lymphocytes, Immunology 28:113, 1975.
Adriamycin and cardiac toxicity To the Editor: In their article, "Adriamycin cardiotoxicity in a child with Wilms tumor," Dr. Gerber and associates ~ presented a case of cardiomyopathy at a level (350 m g / m ~) below the recommended safe norm for the drug (500 mg/m~-). Their patient had received previous irradiation. Irradiation and concurrent cyclophosphamide therapy have been associated with Adriamyein cardiomyopathy at levels below the suggested value and might account for their observation. ~ We have recently had experience with a three-year-old boy
5 18
Letters to the Editor
with acute leukemia who developed signs of cardiomyopathy at a "low" dose of Adriamycin. In contrast, this patient had not received irradiation nor cyclophosphamide. During his sevenmonth course, Patient T. B. received a total dose of 135 mg (270 mg/m=') of Adriamycin and 60 mg (120 m g / m ~) of Daunomycin. This is a total cumulative dose of 390 m g / m ~. Adriamycin is a closely related analog of Daunomycin with similar pharmokinetics. There is evidence that the toxicity results for aglycones of both. 3 The clinical course, cardiotoxicity, pathology, and electron microscopy are identical for both medications. We consider these drugs as having cumulative effects and would utilize the same maximum dose (500 mg/m'-') as if used singly. We would like to re-emphasize Dr. Gerber's conclusion. "The assumption that a total dose of Adriamycin less than 500 m g / m ~ is safe in terms of cardiac toxicity may n o t be valid." It is important to emphasize this restricting aspect of Adriamycin therapy. Unfortunately, there is no clearcut e,arly indication of incipient cardiomyopathy. The electrocardiogram, roentgenogram, echocardiogram, and physical examination demonstrated the signs and symptoms of cardiomyopathy and at present there are no reproducible early clues of developing cardiac dysfunction. Robert P. Rieker, M.D. Assistant Professor of Pediatrics Richard B. Patterson, M.D. Professor of Pediatrics Bowman Gray School of Medicine Winston-Salem, N.C. 27103 REFERENCES
1.
2.
3.
Gerber MA, Gilbert EM, and Chung K J: Adriamycin cardiotoxicity in a child with Wilms tumor, J P:nDiArn 87:629, 1975. Gilladoga AC, Manuel C, Tan CC, Wollner N, and Murphy ML: Cardiotoxicity o f Adriamycin (NSC-123127) in children, Cancer Chemother Rep Part 3, 6:209, 1975. Herman E, Mhatre R, Lee IP, Vick J, and Waravdekar VS: A comparison of the cardiovascular actions of Daunomycin, Adriamycin and N-Acetyldaunomycin in hamsters and monkeys, Pharmacology 6:230, 1971.
Electroencephalogram in hypothyroidism in the neonate To the Editor: We read with interest the article entitled "Congenital hypothyroidism-signs and symptoms in the newborn period," by Smith and associates' which appeared in the December issue of TI~E JOURNAL. We have recently encountered two patients with congenital hypothyroidism and noted two other abnormalities which add to the spectrum of the disease. Initial electroencephalographic examination revealed generalized slowing of wave activity. Ten days after replacement thyroid therapy, there was a definite increase in theta and delta activity.
The Journal of Pediatrics September 1976
As thyroid hormone studies became normal, the electroencephalogram reverted to a normal pattern. Electrocardiographic monitoring showed large, "domeshaped" T waves in lead II, the so-called "Mosque sign. TM This abnormality reverted to normal during the second week of replacement therapy. Steven C. Shapiro, M.D. Gilbert L Martin, M.D. Magan Medical Clinic, Inc. 420 West Rowland St. Covina, Calif. 91723 REFERENCES
1.
2.
Smith DW, Klein AM, Henderson JR, and Myrianthopoulos NC: Congenital hypothyroidism signs and symptoms in the newborn period, J PEDIATR 87:958, 1975. Ertugrul A: A new electrocardiographic observation in infants and children with hypothyroidism, Pediatrics 37:669, 1966.
Host inhibitory or blocking factor in subacute sclerosing panencephalitis To the Editor: The article by Steele and co-workers' expands the increasing body of evidence that an altered cellular immune response is important in the pathogenesis of subacute sclerosing panencephalitis (SSPE). Although children with this disease may not have a basic immune defect, the evidence presented in this article and others ~ has led to the conclusion that an effective host response to the SSPE virus is somehow prevented. We have recdhtly reported :' a heat-stable blocking factor in the plasma of eight patients with SSPE tha~ interfered with lymphocyte reactivity to phytohemagglutinin and in mixed lymphocyte cultures, in vitro assays of immune function. The amount of blocking factor increased with increasing activity or duration of disease; patients with more advanced disease had greater degrees of blocking. Steele and associates state that a blocking factor is "not universally demonstrable" in SSPE patients. Perhaps this is due to the fact that some patients have been studied during the early stages o f disease. Steele does not comment upon the stage of disease when their patients were studied or when the blocking factor was demonstrated. The blocking factor has not yet been completely characterized, but as suggested, a high-molecular weight immunoglobulin or an antigen-antibody complex seem the most likely possibilities. Continuing work in our laboratory suggests that the blocking factor might be an antigen-antibody complex involving theta antigen. Whatever the nature of the blocking factor, we would agree with Steele and associates that such a compound probably contributes to the pathogenesis of SSPE by preventing an effective host response to the SSPE virus. Therefore, specific