Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts.
Imatinib, an inhibitor of PDGF-Rbeta and other tyrosine kinase receptors, has been shown to decrease microvessel density and interstitial fluid pressure in solid tumours, thereby improving subsequent delivery of small molecules. The purpose of this study was to test whether pretreatment with imatinib increases the efficacy of traditional chemotherapy in mice bearing non-small cell lung carcinoma xenografts, and to investigate the effects of imatinib on liposomal drug delivery. Efficacy treatment groups included (n=9-10): saline control, imatinib alone (oral gavage, 100 mg kg(-1) x 7 days), docetaxel alone (10 mg kg(-1) i.p. 2 x /week until killing), and imatinib plus docetaxel (started on day 7 of imatinib). Tumours were monitored until they reached four times the initial treatment volume (4 x V) or 28 days. A separate experiment compared tumour doxorubicin concentrations (using high performance liquid chromatography) 24 h after treatment with liposomal doxorubicin alone (6 mg kg(-1) i.v., n=9) or imatinib plus liposomal doxorubicin (n=16). Imatinib plus docetaxel resulted in significantly improved antitumour efficacy (0/10 animals reached 4 x V by 28 days) when compared to docetaxel alone (3/9 reached 4 x V, P=0.014) or imatinib alone (9/10 reached 4 x V, P=0.025). Pretreatment with imatinib also significantly increased tumour concentrations of liposomal doxorubicin. Overall, these preclinical studies emphasise the potential of imatinib as an adjunct to small molecule or liposomal chemotherapy.
Vlahovic
G
G
Department of Medicine - Oncology, Duke University Medical Center, Durham, NC 27710, USA. vlaho001@mc.duke.edu
Ponce
A M
AM
Rabbani
Z
Z
Salahuddin
F K
FK
Zgonjanin
L
L
Spasojevic
I
I
Vujaskovic
Z
Z
Dewhirst
M W
MW
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D008081:Liposomes; D010879:Piperazines; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D000068877:Imatinib Mesylate
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