Inflammation and altered drug clearance in cancer: transcriptional repression of a human CYP3A4 transgene in tumor-bearing mice.
A tumor-associated inflammatory response has recently been found to contribute to the considerable interindividual variability in cytotoxic drug clearance seen in cancer patients. Circulating inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6), correlate with excessive drug toxicity caused by reduced CYP3A4-mediated metabolism. This article outlines the use of a transgenic mouse model of human CYP3A4 regulation to demonstrate that extrahepatic tumors elicit an inflammatory response, leading to transcriptional repression of the CYP3A4 gene as well as of other drug clearance pathways.
Robertson
G R
GR
Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney at Concord RG Hospital, Concord, New South Wales, Australia. grobertson@med.usyd.edu.au
Liddle
C
C
Clarke
S J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D019076:Transgenes / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human