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


METHODS
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 kinase inhibitors may not be the best schedule with which to combine such agents with taxanes.
Solit
David B
DB
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. solitd@mskcc.org
She
Yuhong
Y
Lobo
Jose
J
Kris
Mark G
MG
Scher
Howard I
HI
Rosen
Neal
N
Sirotnak
Frank M
FM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000473:pathology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D000077156:Gefitinib; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011799:Quinazolines; D017239:Paclitaxel; D000077156:Gefitinib