Serum levels of NFkappaB and pro-inflammatory cytokines following administration of mucotoxic drugs.
BACKGROUND
Alimentary tract (AT) mucositis is a serious complication of cancer treatment. Determining changes that occur in the AT can be difficult as invasive procedures are usually contraindicated in these patients. Changes in tissue levels of the transcription factor NFkappaB and pro-inflammatory cytokines have been demonstrated. The aims of this study were to determine whether changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 following administration of different drugs predicted histological evidence of tissue damage.


RESULTS
Changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 were observed following administration of each drug. These changes differed according to the drug administered. In most instances, peaks in serum levels occurred following initial histological changes, Although following MTX administration, serum IL-1beta peaked before histological changes and following 5-FU administration, serum NFkappaB, TNF, IL-1beta and IL-6 all peaked before histological evidence of tissue damage.


METHODS
Female DA rats (n = 243) were given a single dose of irinotecan (200 mg/kg intraperitoneally), methotrexate (1.5 mg/kg intramuscularly) or 5-fluorouracil (150 mg/kg intraperitoneally) and killed 30, 60, 90 minutes, 2, 6, 12, 24, 48 or 72 hours later. Control rats received no treatment. Blood samples were taken via cardiac puncture and centrifuged at 5000 rpm to collect serum. Serum levels of NFkappaB, and pro-inflammatory cytokines were measured by ELISA.


CONCLUSIONS
Although changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 preceded histological changes in tissues, it was concluded that measurement of these factors was not useful in predicting mucosal damage because of the critical time constraints between detectable serun changes and the histological damage. This study highlighted the systemic effects of the drugs. Further studies are required to determine the possible relationships between different toxicities and determine how, once these links are known, patient management can be improved.
Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, South Australia, Australia. richard.logan@adelaide.edu.au
Richard M
RM
Logan
Andrea M
AM
Stringer
Joanne M
JM
Bowen
Rachel J
RJ
Gibson
Stephen T
ST
Sonis
Dorothy M K
DM
Keefe
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000097:blood*; D004848:Epithelium / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D041981:Gastrointestinal Tract / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D000077146:Irinotecan; D008727:Methotrexate / Q000494:pharmacology; D016328:NF-kappa B / Q000097:blood*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin; D008727:Methotrexate