IMedical
Hypotheses
I
1
Medical Hypothu8# (1991) 35.146447 oLonupnnGmupuKud1991
Dementia in Cancer Patients Undergoing Chemotherapy: Implication of Free Radical Injury and Relevance to Alzheimer Disease J. BACKON Mount Pleasant Hospital Addiction Study Foundation, Lynn, MA, USA (Address for correspondence: POE 16336, Jerusalem, Israel)
Abstract - A number of neurological disorders including Alzheimer and Parkinson disease have been suggested to be caused by processes leading to lipid peroxidation. Other theories implicate the accumulation of damaged DNA, resulting from a defect in DNA repair, in the pathogenesis of these disorders. I suggest that these theories might be related, since the hydroxy free radical is known to attack DNA and inactivate enzymes so that oxygen metabolism has the potential to interfere with the maintenance of genomic integrity. Since psychometric intelligence correlates highly with erythrocyte glutathione peroxidase activity, a free radical scavenger, perhaps this might explain the marked intellectual impairment caused by chemotherapeutic agents such as cytosine arabinoside, as well as in Alzheimer disease.
Davis et al (1) recently reported a high percentage of dementia in cancer patients undergoing chemotherapy, and stressed the importance of understanding the neurotoxic effects of chemotherapeutic agents. I propose that these findings could be understood by the mechanism of free radical damage and, furthermore, that this phenomenon might shed light on the etiology of Alzheimer and other forms of dementia. A number of neurological disorders, including Alzheimer and Parkinson disease, have been suggested to be caused by processes leading to lipid peroxidation (2). A number of chronic neurological degenerative disorders, including Parkinson disease, Cockayne syndrome, familial dysautonomia, amyotropic lateral sclerosis, and senile dementia of the Date received 12 June 1988 Date accepted 15 November 1988
Alzheimer type, may be due to the accumulation of damaged DNA, resulting from a defect in DNA repair (3,4, 5). These concepts may be related. Malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, is a reactive electrophile that can form a conjugated Schiff base with amino groups of amino acids. The hydroxy free radical is known to attack DNA and inactivate enzymes so that oxygen metabolism has the potential to interfere with the maintenance of genomic integrity (6). Anticancer drugs too, seem to exert their antitumor action(s) by free radical generation and lipid peroxidation (7.8). Free oxygen radicals decrease electrical resistance of microvascular endothelium in brain (9)
146
147
DEMENTIA IN CANCER PATIENTS UNDERGOING CHEMCrTHERAPY
a8 well as cause a breakdown of the transmembrane ion gradient (10). Since psychometric intelligence correlates highly with erythrocyte glutathione peroxidase activity (11). which is a free radical scavenger, perhaps this might explain the marked intellectual impairment caused by chemotherapeutic agents such as cytosine arabinoside. Our group has suggested that the same mechanism might be involved in the confusional state following alcohol intoxication since ethanol is a known activator of lipid peroxidation.
References Davis BD, Femandez F, Adams F. et al. Diagnosis of dementia in cancer patients. Psychosomatics 28: 175-179, 1987. Kish SJ, MoritoCLH, Homykiewicz 0. Brain glutathione peroxidase in neurodegenerative disorders. Neurochem Path01 4: 23-28, 1986. Robbins JH. Hypersensitivity to DNA damaging agents in primary degeneration of excitable tissue. p 671 in Cellular Responses to DNA Damage (UCLA Symposium on Molecular
4.
5. 6.
7.
8. 9.
10. 11.
and Cellular Biology, Vol II (Fried&g EC, Bridges BA eds) Alan Liss, New York. 1983. Scud&o DA, Meyer SA. Clatterbuck BE et al. Hypersmsitivity to N-methyl-N-nitro-N-nitrosoguanidine in fibroblasts from patients with Huntington disease, familial dysautoncmia. and other primary neuronal degenerations. Proc Natl Acad Sci USA 78: 6451-55, 1981. Robison SH, Bradley WG. DNA damage and chronic neuronal degeneration. J Neurol Sci 64: 11-20, 1984. Ames BN. Dietary carcinogens and anticarcinogens, oxygen radicals and degenerative disease. Science 221: 1256-1264, 1983. Mimnangh EC. Kennedy KA, Tmsh MA, Sinha BK. Adriamy -tin-enhanced membrane lipid peroxidation in isolated rat nuclei. Cancer Res 45: 32963304. 1985. Zweier JL. Iron-mediated formation of an oxidized adriamycin free radical. Biochim Biophysics Acta 839: 209-213, 1985. Olesen SP Free oxygen radicals decrease electrical resistance of microvascular endothelium in brain. Acta Physiol Stand 129: 181-187, 1987. Weiss S. Oxygen, ischemia and inflammation. Acta Physiol Stand (Suppl 548) 126: 9-37, 1986. Weiss V. Psychometric intelligence correlates with interindividual different rates of lipid peroxidation. Biomed B&him Acts 434: 755-763, 1984.
Hypotheses
I
1
Medical Hypothu8# (1991) 35.146447 oLonupnnGmupuKud1991
Dementia in Cancer Patients Undergoing Chemotherapy: Implication of Free Radical Injury and Relevance to Alzheimer Disease J. BACKON Mount Pleasant Hospital Addiction Study Foundation, Lynn, MA, USA (Address for correspondence: POE 16336, Jerusalem, Israel)
Abstract - A number of neurological disorders including Alzheimer and Parkinson disease have been suggested to be caused by processes leading to lipid peroxidation. Other theories implicate the accumulation of damaged DNA, resulting from a defect in DNA repair, in the pathogenesis of these disorders. I suggest that these theories might be related, since the hydroxy free radical is known to attack DNA and inactivate enzymes so that oxygen metabolism has the potential to interfere with the maintenance of genomic integrity. Since psychometric intelligence correlates highly with erythrocyte glutathione peroxidase activity, a free radical scavenger, perhaps this might explain the marked intellectual impairment caused by chemotherapeutic agents such as cytosine arabinoside, as well as in Alzheimer disease.
Davis et al (1) recently reported a high percentage of dementia in cancer patients undergoing chemotherapy, and stressed the importance of understanding the neurotoxic effects of chemotherapeutic agents. I propose that these findings could be understood by the mechanism of free radical damage and, furthermore, that this phenomenon might shed light on the etiology of Alzheimer and other forms of dementia. A number of neurological disorders, including Alzheimer and Parkinson disease, have been suggested to be caused by processes leading to lipid peroxidation (2). A number of chronic neurological degenerative disorders, including Parkinson disease, Cockayne syndrome, familial dysautonomia, amyotropic lateral sclerosis, and senile dementia of the Date received 12 June 1988 Date accepted 15 November 1988
Alzheimer type, may be due to the accumulation of damaged DNA, resulting from a defect in DNA repair (3,4, 5). These concepts may be related. Malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, is a reactive electrophile that can form a conjugated Schiff base with amino groups of amino acids. The hydroxy free radical is known to attack DNA and inactivate enzymes so that oxygen metabolism has the potential to interfere with the maintenance of genomic integrity (6). Anticancer drugs too, seem to exert their antitumor action(s) by free radical generation and lipid peroxidation (7.8). Free oxygen radicals decrease electrical resistance of microvascular endothelium in brain (9)
146
147
DEMENTIA IN CANCER PATIENTS UNDERGOING CHEMCrTHERAPY
a8 well as cause a breakdown of the transmembrane ion gradient (10). Since psychometric intelligence correlates highly with erythrocyte glutathione peroxidase activity (11). which is a free radical scavenger, perhaps this might explain the marked intellectual impairment caused by chemotherapeutic agents such as cytosine arabinoside. Our group has suggested that the same mechanism might be involved in the confusional state following alcohol intoxication since ethanol is a known activator of lipid peroxidation.
References Davis BD, Femandez F, Adams F. et al. Diagnosis of dementia in cancer patients. Psychosomatics 28: 175-179, 1987. Kish SJ, MoritoCLH, Homykiewicz 0. Brain glutathione peroxidase in neurodegenerative disorders. Neurochem Path01 4: 23-28, 1986. Robbins JH. Hypersensitivity to DNA damaging agents in primary degeneration of excitable tissue. p 671 in Cellular Responses to DNA Damage (UCLA Symposium on Molecular
4.
5. 6.
7.
8. 9.
10. 11.
and Cellular Biology, Vol II (Fried&g EC, Bridges BA eds) Alan Liss, New York. 1983. Scud&o DA, Meyer SA. Clatterbuck BE et al. Hypersmsitivity to N-methyl-N-nitro-N-nitrosoguanidine in fibroblasts from patients with Huntington disease, familial dysautoncmia. and other primary neuronal degenerations. Proc Natl Acad Sci USA 78: 6451-55, 1981. Robison SH, Bradley WG. DNA damage and chronic neuronal degeneration. J Neurol Sci 64: 11-20, 1984. Ames BN. Dietary carcinogens and anticarcinogens, oxygen radicals and degenerative disease. Science 221: 1256-1264, 1983. Mimnangh EC. Kennedy KA, Tmsh MA, Sinha BK. Adriamy -tin-enhanced membrane lipid peroxidation in isolated rat nuclei. Cancer Res 45: 32963304. 1985. Zweier JL. Iron-mediated formation of an oxidized adriamycin free radical. Biochim Biophysics Acta 839: 209-213, 1985. Olesen SP Free oxygen radicals decrease electrical resistance of microvascular endothelium in brain. Acta Physiol Stand 129: 181-187, 1987. Weiss S. Oxygen, ischemia and inflammation. Acta Physiol Stand (Suppl 548) 126: 9-37, 1986. Weiss V. Psychometric intelligence correlates with interindividual different rates of lipid peroxidation. Biomed B&him Acts 434: 755-763, 1984.
