Anticancer efficacy of the irreversible EGFr tyrosine kinase inhibitor PD 0169414 against human tumor xenografts

Cancer Chemother Pharmacol. 2000;45(3):231-8. doi: 10.1007/s002800050034.


Purpose: The involvement of the EGF receptor (EGFr) family of receptors in cancers suggests that a selective inhibitor of the tyrosine kinase activity of the EGFr family could have a therapeutic effect. PD 0169414, an anilinoquinazoline, is a potent irreversible inhibitor of the EGFr family tyrosine kinase activity with IC(50) values of 0.42 nM against the isolated EGF receptor, and 4.7 nM and 22 nM against EGF- and heregulin-mediated receptor phosphorylation in A431 and MDA-MB-453 cells, respectively.

Methods and results: Oral administration of 260 mg/kg per day PD 0169414 for 15 days to animals bearing advanced-stage A431 epidermoid carcinoma produced a 28.2-day delay in tumor growth and resulted in three complete and three partial tumor regressions in six animals. Toxicity at this dose level was limited to <6% loss of initial body weight. Doses of 160 and 100 mg/kg per day produced tumor growth delays of 29.5 and 20.9 days and two and one complete regressions in six animals, respectively. Subcutaneous, intraperitoneal, and oral routes of administration have also shown in vivo antitumor activity of PD 0169414 in a panel of human tumor xenografts. Responsive tumor lines include A431 (human epidermoid carcinoma), H125 (NSCL carcinoma), MCF-7 and UISO-BCA1 (human breast carcinoma), and SK-OV-03 (human ovarian carcinoma). The therapeutic effect ranged from delayed tumor growth (6.4 days delayed tumor growth for 14 days of treatment) to tumor regressions (32.2 days delayed tumor growth and five partial regressions in six animals) in these model systems.

Conclusion: PD 0169414 is a specific, irreversible inhibitor of EGFr family tyrosine kinases with significant in vivo activity against a variety of relevant human tumor xenografts.

Publication types

  • Comparative Study

MeSH terms

  • 3T3 Cells
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Area Under Curve
  • Drug Administration Routes
  • Drug Administration Schedule
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / drug effects*
  • ErbB Receptors / metabolism
  • Humans
  • Infusion Pumps, Implantable
  • Liver / drug effects
  • Liver / pathology
  • Mice
  • Mice, Inbred ICR
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Phosphorylation / drug effects
  • Quinazolines / blood
  • Quinazolines / pharmacokinetics*
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Transplantation, Heterologous
  • Treatment Outcome
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • PD 0169414
  • Quinazolines
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases