Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel Journal Article


Authors: Solit, D. B.; She, Y.; Lobo, J.; Kris, M. G.; Scher, H. I.; Rosen, N.; Sirotnak, F. M.
Article Title: Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel
Abstract: Purpose: Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Continuous inhibition of EGFR signaling is thought necessary for optimal inhibition of tumor cell proliferation. We hypothesized that continuous gefitinib may antagonize the effects of cytotoxics that inhibit tumor cells in other phases of the cell cycle. Furthermore, we hypothesized that intermittent dosing would allow for dose escalation and greater inhibition of EGFR-dependent antiapoptotic pathways. Experimental Design: To test these assertions, we compared combinations of paclitaxel and gefitinib using either intermittent or continuous dosing schedules in mice. Results: We found that when used in combination with paclitaxel, pulsatile gefitinib was significantly superior to continuous dosing. When gefitinib was administered for one or two consecutive days before paclitaxel, much higher doses could be given safely. Two days of gefitinib treatment before paclitaxel was most effective, causing significantly greater mean tumor regression and a higher percentage of complete responses than other schedules. Conclusions: The results suggest that the dose and schedule of an EGFR inhibitor required to effectively inhibit proliferation may differ from that required to stimulate apoptosis or to induce other effects. The former may require continuous EGFR inhibition to maintain cell cycle arrest, whereas sensitization to apoptosis may be optimally induced by profound but temporary inhibition of survival pathways. Our data suggest that the effects of receptor inhibition vary as a function of dose and schedule and that continuous administration of tyrosine idnase inhibitors may not be the best schedule with which to combine such agents with taxanes. ©2005 American Association for Cancer Research.
Keywords: controlled study; human cell; cytotoxic agent; dose response; drug efficacy; nonhuman; antineoplastic agents; paclitaxel; mouse; animals; mice; animal tissue; cell cycle; antineoplastic combined chemotherapy protocols; drug administration schedule; animal experiment; animal model; antineoplastic agents, phytogenic; cytotoxicity; tumor regression; tumor cells, cultured; breast neoplasms; cancer inhibition; statistical significance; mice, nude; gefitinib; tumor cell; transplantation, heterologous; intermethod comparison; drug dose regimen; quinazolines; drug pulse therapy; drug interactions; epidermal growth factor receptor kinase inhibitor; drug intermittent therapy; drug sensitization
Journal Title: Clinical Cancer Research
Volume: 11
Issue: 5
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2005-03-01
Start Page: 1983
End Page: 1989
Language: English
DOI: 10.1158/1078-0432.ccr-04-1347
PUBMED: 15756024
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 68" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Neal Rosen
    359 Rosen
  2. David Solit
    431 Solit
  3. Yuhong She
    31 She
  4. Howard Scher
    817 Scher
  5. Mark Kris
    597 Kris
  6. Francis M Sirotnak
    113 Sirotnak
  7. Jose Manuel Lobo
    12 Lobo