Circadian variation of topoisomerase II-alpha in human rectal crypt epithelium: implications for reduction of toxicity of chemotherapy.
Topoisomerase II-alpha is a target of common chemotherapeutic agents such as doxorubicin and etoposide, which induce DNA damage by altering the activity of this enzyme. We took rectal biopsies at 4-hour intervals over a 24-hour period (seven total) from each of 10 healthy volunteers and examined immunoperoxidase-stained coded anti-topoisomerase II-alpha-stained sections. A significant circadian periodicity was seen in the number of rectal crypt epithelial cell nuclei that were stained (P =.01). Mean peak staining was at 7:23 a.m. +/- 45 minutes, and the mean rate of change (difference between peak and trough expression) was 40%. Topoisomerase II-alpha expression in rectal epithelium has a significant circadian variation similar to that of tritiated thymidine incorporation. Although direct confirmation is needed, giving topoisomerase II-targeted chemotherapeutic agents at the proper time of day might reduce their mucositis side effects.
Clayton
Frederic
F
Department of Pathology, Salt Lake Veterans Administration Hospital, Salt Lake City, Utah 84148, USA.
Tessnow
Kathryn A
KA
Fang
John C
JC
Holden
Joseph A
JA
Moore
John G
JG
D000293:Adolescent; D000328:Adult; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019454:Chronotherapy / Q000379:methods; D002940:Circadian Rhythm / Q000502:physiology*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis* / Q000187:drug effects; D004268:DNA-Binding Proteins; D004848:Epithelium / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D012007:Rectum / Q000201:enzymology*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004250:DNA Topoisomerases, Type II