Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors

Abstract

Antibodies and other macromolecular therapeutics can gain access to tumor cells via leaky tumor vessels. Inhibition of vascular endothelial growth factor (VEGF) signaling can reduce the vascularity of tumors and leakiness of surviving vessels, but little is known about how these changes affect the distribution of antibodies within tumors. We addressed this issue by examining the distribution of extravasated antibodies in islet cell tumors of RIP-Tag2 transgenic mice and implanted Lewis lung carcinomas using fluorescence and confocal microscopic imaging. Extravasated nonspecific immunoglobulin G (IgG) and antibodies to fibrin or E-cadherin accumulated in irregular patchy regions of stroma. Fibrin also accumulated in these regions. Anti-E-cadherin antibody, which targets epitopes on tumor cells of RIP-Tag2 adenomas, was the only antibody to achieve detectable levels within tumor cell clusters at 6 hours after i.v. injection. Treatment for 7 days with AG-013736, a potent inhibitor of VEGF signaling, reduced the tumor vascularity by 86%. The overall area density of extravasated IgG/antibodies decreased after treatment but the change was less than the reduction in vascularity and actually increased when expressed per surviving tumor vessel. Accumulation of anti-E-cadherin antibody in tumor cell clusters was similarly affected. The patchy pattern of antibodies in stroma after treatment qualitatively resembled untreated tumors and surprisingly coincided with sleeves of basement membrane left behind after pruning of tumor vessels. Together, the findings suggest that antibody transport increases from surviving tumor vessels after normalization by inhibition of VEGF signaling. Basement membrane sleeves may facilitate this transport. Antibodies preferentially distribute to tumor stroma but also accumulate on tumor cells if binding sites are accessible. (Cancer Res 2006; 66(3): 1434-45)

Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib

“…This suggests that the longer-term exposure to axitinib increases the efficiency of blood flow and 4-OH-CPA transport in the remaining tumor blood vessels. Increases in transport efficiency per surviving vessel have been reported for the delivery of IgG protein and 50-nm microspheres to axitinib-treated tumors (35). Axitinib also induces multiple morphological changes, including an increase in the uniformity of tumor blood vessel diameter, a decrease in blood vessel tortuosity and in the number of leaky vessels, and a closer association between pericytes and endothelial cells (16).…”

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…In addition, elegant preclinical work examining the role of Yuan et al 1996;Tong et al 2004;Dickson et al 2007b;Taguchi et al 2008;Falcon et al 2009;Juan et al 2009;Kamoun et al 2009;Chae et al 2010;Koh et al 2010;Primo et al 2010. b Jain et al 1998;Izumi et al 2002;Delmas et al 2003;Qayum et al 2009. d Inai et al 2004;Tong et al 2004;Nakahara et al 2006;Dickson et al 2007b;Dings et al 2007;Fischer et al 2007;Zhou et al 2008;Falcon et al 2009;Juan et al 2009;Kamoun et al 2009;Ohta et al 2009;Zhou and Gallo 2009;Chae et al 2010;Primo et al 2010. Lee et al 2000;Winkler et al 2004;Dings et al 2007;Fischer et al 2007;Eichhorn et al 2008;Batra et al 2009;Skuli et al 2009;McGee et al 2010.…”

“…j Teicher et al 1995bJain et al 1998;Bernsen et al 1999;Cohen-Jonathan et al 2001;Delmas et al 2003;Ansiaux et al 2005Ansiaux et al , 2006Pore et al 2006b;Segers et al 2006;Cerniglia et al 2009;Qayum et al 2009;Cham et al 2010. k Ader et al 2003;Hamzah et al 2008;Kashiwagi et al 2008;Stockmann et al 2008;Maione et al 2009;Mazzone et al 2009;Skuli et al 2009;Tsukada et al 2009;Rolny et al 2011. l Yuan et al 1996Lee et al 2000;Wildiers et al 2003;Tong et al 2004;Nakahara et al 2006;Dickson et al 2007b;Kurozumi et al 2007;Taguchi et al 2008;Zhou et al 2008;Kamoun et al 2009;Ohta et al 2009;Gallo 2009. m Jain et al 1998;Izumi et al 2002;Ansiaux et al 2005;Salnikov et al 2005;Bhattacharya et al 2008Bhattacharya et al , 2009Schnell et al 2008;Cerniglia et al 2009. n Dickson et al 2007c;Kashiwagi et al 2008;di Tomaso et al 2009;…”

Radiation to control transgene expression in tumors

“…54 Vasculature-induced delivery limitations have also shown to be improved with the concomitant administration of anti-VEGF, pro-inflammatory cytokines and vasoactive agents. 55,56 Normalization of the vasculature by anti-angiogenic therapies indeed resulted in improved tumor oxygenation, enhanced drug absorption and increased radiosensitivity. 57,58 Because the blood vessel network is responsible for systemic drug delivery, the impact of previous therapeutic intervention on the tumor vasculature is an important factor as to the efficacy of the adjuvant administration of novel therapeutics, especially since novel anti-cancer agents are more than likely to enter clinical trials in patients with treatment-refractory tumors.…”