Architectural heterogeneity in tumors caused by differentiation alters intratumoral drug distribution and affects therapeutic synergy of antiangiogenic organoselenium compound.
Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium. Marked potentiation of antitumor activity was observed in H69 tumors that exhibited a well-vascularized, poorly differentiated phenotype. In comparison, modulation of chemotherapeutic efficacy by antiangiogenic selenium was generally lower or absent in well-differentiated tumors with multiple avascular hypoxic, differentiated regions. Tumor histomorphologic heterogeneity was found prevalent in the clinical samples studied and represents a primary and critical physiological barrier to chemotherapy.
Rustum
Youcef M
YM
Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Tóth
Károly
K
Seshadri
Mukund
M
Sen
Arindam
A
Durrani
Farukh A
FA
Stott
Emily
E
Morrison
Carl D
CD
Cao
Shousong
S
Bhattacharya
Arup
A
Neoplasia. 2008 Aug;10(8):857-65
18670644
Cancer Chemother Pharmacol. 2010 Oct;66(5):899-911
20066420
Br J Nutr. 2004 Jan;91(1):11-28
14748935
Cancer Cell. 2009 Mar 3;15(3):220-31
19249680
Curr Opin Clin Nutr Metab Care. 2008 Nov;11(6):718-26
18827575
Oncogene. 2006 Apr 20;25(17):2509-19
16518418
J Natl Cancer Inst. 2007 Oct 3;99(19):1441-54
17895480
Clin Cancer Res. 2004 Feb 1;10(3):1121-9
14871992
Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):97-103
17056201
Clin Colorectal Cancer. 2009 Jul;8(3):155-62
19632930
Clin Cancer Res. 2005 Oct 15;11(20):7220-5
16243791
Nature. 2000 Sep 14;407(6801):249-57
11001068
Microvasc Res. 2005 Jul;70(1-2):116-20
16137719
Clin Cancer Res. 2003 Nov 15;9(15):5666-74
14654550
Clin Cancer Res. 2004 Apr 1;10(7):2561-9
15073137
Magn Reson Med. 1997 Feb;37(2):236-42
9001148
J Clin Oncol. 1991 Jan;9(1):50-61
1702146
Neoplasia. 2006 Jul;8(7):534-42
16867215
Nat Med. 2001 Sep;7(9):987-9
11533692
Nat Rev Cancer. 2004 Oct;4(10):806-13
15510161
Nat Rev Cancer. 2007 Jun;7(6):475-85
17522716
Biochim Biophys Acta. 2009 Apr;1795(2):162-72
19344680
Int J Cancer. 2004 Nov 20;112(4):570-6
15382037
Cancer Chemother Pharmacol. 2008 Aug;62(3):499-508
17989978
Clin Cancer Res. 2004 Dec 1;10(23):8005-17
15585636
Clin Cancer Res. 2008 Jun 15;14(12):3926-32
18559614
Appl Immunohistochem Mol Morphol. 2010 Jul;18(4):375-81
20216402
Nat Clin Pract Oncol. 2009 Jan;6(1):43-52
18982000
Nature. 2009 Mar 19;458(7236):290-2
19295595
Cancer Res. 1993 May 15;53(10 Suppl):2204-7
8485703