Back to Search
Start Over
Therapeutic efficiency of everolimus and lapatinib in xenograft model of human colorectal carcinoma with KRAS mutation.
- Source :
-
Fundamental & clinical pharmacology [Fundam Clin Pharmacol] 2013 Aug; Vol. 27 (4), pp. 434-42. Date of Electronic Publication: 2012 Mar 28. - Publication Year :
- 2013
-
Abstract
- KRAS mutation is a negative predictive prognostic factor during metastatic colorectal cancer treatment with antiepidermal growth factor receptor antibodies. For affected patients, new therapeutics must be explored. Our objective was to study efficacy of two drugs with different mechanisms of action, everolimus (mTOR inhibitor) and lapatinib (tyrosine kinase inhibitor), in a mouse xenograft model. We chose a model obtained after engraftment of a tumor originating from a human tumor collection. The patient was affected by a metastasis colorectal carcinoma resistant to cetuximab with KRAS mutation. From a previous study in mice, we know that everolimus is a P-glycoprotein (P-gp) substrate and that a lapatinib pretreatment increases significantly (2.6-fold) everolimus AUC by inhibiting its intestinal P-gp efflux. We hence tested the effect of these drugs alone or combined. Mice bearing the xenografts were divided in four groups: control, lapatinib, everolimus, and L/E group (L/E: 2 days of lapatinib 200 mg/kg and then 3 days of everolimus 1 mg/kg). Tumor volumes and treatment toxicities were evaluated. Sixteen days after treatment initiation, the group L/E was the first one in which tumor volume average was significantly lower than the one of control group (193 ± 90 vs. 395 ± 171 mm(3) ; P = 0.0025). After 4 weeks of treatment, inhibition of tumor growth in lapatinib, everolimus, and L/E groups reached, respectively, 49, 53, and 57%. Each drug showed significant antitumor activity. Only moderate hematologic toxicity signs were observed. These results lead to new perspectives for new oral drugs in metastatic KRAS-mutated colorectal cancer resistant to standard chemotherapy.<br /> (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B metabolism
Animals
Colorectal Neoplasms genetics
Colorectal Neoplasms metabolism
Drug Resistance, Neoplasm
Everolimus
Female
Humans
Lapatinib
Mice
Mice, Nude
Mutation
Quinazolines administration & dosage
Sirolimus administration & dosage
Sirolimus pharmacology
Xenograft Model Antitumor Assays
ras Proteins metabolism
Antineoplastic Combined Chemotherapy Protocols pharmacology
Colorectal Neoplasms drug therapy
Quinazolines pharmacology
Sirolimus analogs & derivatives
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1472-8206
- Volume :
- 27
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Fundamental & clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 22458846
- Full Text :
- https://doi.org/10.1111/j.1472-8206.2012.01035.x