title: Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts.
abstract: 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.
authors: Department of Medicine - Oncology, Duke University Medical Center, Durham, NC 27710, USA. vlaho001@mc.duke.edu
authors: G
authors: G
authors: Vlahovic
authors: A M
authors: AM
authors: Ponce
authors: Z
authors: Z
authors: Rabbani
authors: F K
authors: FK
authors: Salahuddin
authors: L
authors: L
authors: Zgonjanin
authors: I
authors: I
authors: Spasojevic
authors: Z
authors: Z
authors: Vujaskovic
authors: M W
authors: MW
authors: Dewhirst
mesh_terms: 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
chemical_list: D001549:Benzamides; D008081:Liposomes; D010879:Piperazines; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D000068877:Imatinib Mesylate
references: N Engl J Med. 2003 Jul 31;349(5):419-21
references: 12890838
references: N Engl J Med. 2002 Jan 10;346(2):92-8
references: 11784875
references: Clin Cancer Res. 2004 Jan 15;10(2):681-90
references: 14760091
references: Nat Med. 2004 Feb;10(2):145-7
references: 14745444
references: Cancer Res. 2004 Apr 15;64(8):2725-33
references: 15087386
references: Magn Reson Med. 2004 Jun;51(6):1153-62
references: 15170835
references: Cancer Res. 2004 Jun 1;64(11):3731-6
references: 15172975
references: Cancer Res. 2004 Jun 15;64(12):4201-8
references: 15205332
references: Cytokine Growth Factor Rev. 2004 Aug;15(4):275-86
references: 15207817
references: Nat Rev Cancer. 2004 Oct;4(10):806-13
references: 15510161
references: J Chromatogr. 1985 Jun 14;341(2):401-9
references: 4030989
references: Br J Cancer. 1988 Jul;58(1):109-13
references: 3166888
references: Cancer Res. 1988 Dec 15;48(24 Pt 1):7022-32
references: 3191477
references: Cancer Res. 1990 Aug 1;50(15):4478-84
references: 2369726
references: Cancer Res. 1992 Sep 15;52(18):5110-4
references: 1516068
references: Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2558-62
references: 7708684
references: Cancer Res. 1995 Sep 1;55(17):3752-6
references: 7641188
references: Ann Biomed Eng. 1996 Jul-Aug;24(4):457-73
references: 8841721
references: Lab Invest. 1997 Nov;77(5):431-6
references: 9389786
references: Semin Radiat Oncol. 1998 Jul;8(3):164-75
references: 9634493
references: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3137-42
references: 10077650
references: Cancer Res. 1999 Aug 1;59(15):3776-82
references: 10446995
references: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11410-5
references: 10500190
references: Cancer Cell. 2004 Dec;6(6):553-63
references: 15607960
references: Science. 2005 Jan 7;307(5706):58-62
references: 15637262
references: Br J Cancer. 2006 Oct 23;95(8):1013-9
references: 17003785
references: J Natl Cancer Inst. 2007 Jan 3;99(1):53-63
references: 17202113
references: Cancer Res. 1994 Jul 1;54(13):3352-6
references: 8012948
references: Cancer Res. 2000 Dec 15;60(24):6950-7
references: 11156395
references: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):149-68
references: 11259838
references: Cancer Res. 2001 Apr 1;61(7):2929-34
references: 11306470
references: Adv Exp Med Biol. 2003;532:141-51
references: 12908555