Cytotoxic Aldehydes as Possible Markers for Childhood Cancer

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Abstract

Concentrations of 22 known aldehydes (byproducts of lipid peroxidation), 5 acyloins, free and total carnitine and acylcarnitines were measured in plasma and urine obtained from pediatric patients with various forms of cancer before any treatment, and following treatment with doxorubicin or daunorubicin. Aldehydes, before the initiation of chemotherapy, were significantly elevated in cancer patients compared to controls. Aldehydes such as hexanal, heptanal, and malondialdehyde were strikingly higher in samples from cancer patients, while trans 4-cis-4-decenal was the prominent aldehyde in the blood of controls. In addition, in each form of cancer the pattern of aldehydes appeared to be unique when compared to controls, or to others forms of cancer. In cancer patients receiving chemotherapy there was a general trend toward a reduction 24 h after both the first and after the fifth doxorubicin dose. These changes however were not significant statistically due to large inter-patient variation. Free and total plasma carnitine levels remained in the normal range, and there were no abnormal acylcarnitines detected in urine. Possible hypotheses to explain the elevations in aldehydes, and the reasons for the changed aldehyde profiles in different forms of cancer are discussed.

Introduction

Free radical-induced oxidation of the membrane lipids leads to the formation of cytotoxic aldehydes, breakdown products of lipid hydroperoxides formed from the reaction of hydroxyl (HȮ) or superoxide radical (O2̇−) with membrane lipids.[1]Aliphatic saturated and unsaturated aldehydes are mainly formed from the degradation of the hydroperoxides of arachidonic acid (20:4), linoleic acid (18:2) and docosahexaeneic acid (22:6).2, 3The aldehydes generated are relatively stable and biologically active, and therefore may be considered as “cytotoxic second messengers.” Since they originate from free radical-induced reactions with cellular lipids, the presence of these aldehydes is considered a marker, and as evidence that free radical-mediated reactions have taken place recently. An increase in aldehyde concentrations implies greater oxidative stress.

It has been reported that human tumor cells produce large amounts of hydrogen peroxide and oxidative stress persists during cancer.4, 5Human renal cell carcinomas have a higher content of the oxidized DNA base, 8-hydroxy-2-deoxyguanosine (8-OH-dG), than nontumor renal tissue.[6]The greater oxidative stress that cancer tissue appears to be exposed to is not adequate to cause extensive death of these cells, possibly because of the altered membrane lipid composition of tumor cells to a less unsaturated form, increased vitamin E, increase in glutathione-S-transferase π (GST-P) and glutathione.7, 8, 9, 10

Drugs used in chemotherapy such as doxorubicin (Adriamycin, DOX) intercalate with DNA base pairs, inhibit DNA synthesis, and prevent DNA replication and transcription, and thus prevent the growth of tumor cells. The major obstacle to the use of DOX has been the finding that it causes a dose-related cardiomyopathy when the dosage approaches or exceeds 300 mg/m2 of body surface area in children, or 550mg/m2 in adults.11, 12, 13, 14Administration of this drug has also been shown to cause the formation of free radicals, and many of the toxic effects of DOX have been attributed to lipid peroxidation injury.

Several recent reports have indicated that l-carnitine administration may be an effective treatment for the prevention of doxorubicin-induced cardiomyopathy.15, 16, 17In patients to whom carnitine was given together with doxorubicin, echocardiographic evidence indicated that myocardial function was improved compared to patients treated with DOX alone.[16]In rats, chronic administration of doxorubicin over a 6–7 week period produced cardiotoxicity.[17]Daily treatment with l-carnitine prevented both the decline in cardiac performance and the histological alterations.[17]The mechanisms by which carnitine exerts these effects are unclear.

In the present experiments we have identified a difference in the plasma aldehyde profile of patients with cancer compared to noncancer patients (controls). We also investigated changes in l-carnitine, and in lipid peroxidation after treatment with DOX.

Section snippets

Protocol

Plasma samples were collected from pediatric cancer patients undergoing treatment at The Hospital For Sick Children, Toronto. A total of twenty seven (27) children were investigated. Children between 1–18 years of age (mean ± SD = 9 ± 5.5 yrs) receiving doxorubicin for the first time were eligible, whether or not they were receiving other drugs. Since treatment regimens were interspersed with surgery, timing between first and last DOX dose, and collections of specimens was not uniform. Age and

Results

All cancer patients: The total plasma aldehyde concentration indicated that when all cancer patients were combined into a single group, patients with cancer had higher levels of total aldehydes than controls however, the changes were not statistically significant. Aldehyde profiles for all cancer patients were also different from controls. There was an increase in plasma hexanal, heptanal and malondialdehyde concentrations compared to noncancer patients. The major aldehyde present in controls

Discussion

The present study suggests a significant and cancer specific elevation in plasma aldehydes in cancer patients when compared to noncancer controls. The patterns of aldehyde concentrations were different in cancer patients from noncancer controls suggesting a higher production or reduced elimination of the products of free radical reactions in patients with cancer.

Although a relationship between increases in free radical-mediated lipid peroxidation and cancer or other diseases of old age has been

Acknowledgements

Partial support for this work by Sigma Tau Pharmaceuticals, Inc. is gratefully acknowledged.

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