TY - JOUR
T1 - Cyclophosphamide enhances human tumor growth in nude rat xenografted tumor models
AU - Wu, Yingjen Jeffrey
AU - Muldoon, Leslie L.
AU - Dickey, Dana Thomas
AU - Lewin, Seth J.
AU - Varallyay, Csanad G.
AU - Neuwelt, Edward A.
N1 - Funding Information:
Abbreviations: CTX, cyclophosphamide; GSH, glutathione; MRI, magnetic resonance imaging; SCLC, small cell lung carcinoma; TE, echo time; TR, relaxation time; VEGF, vascular endothelial growth factor Address all correspondence to: Edward A. Neuwelt, MD, Department of Neurology and Blood Brain Barrier Program, Oregon Health and Sciences University, 3181 Sam Jackson Parkway Road, L603, Portland, OR 97239. E-mail: neuwelte@ohsu.edu 1Funding: This work was supported by a Veterans Administration Merit Review grant and National Institutes of Health grants NS33618, NS53468, and NS44687 from the National Institute of Neurological Disorders and Stroke to E.A.N. Received 21 October 2008; Revised 14 November 2008; Accepted 18 November 2008 Copyright © 2009 Neoplasia Press, Inc. All rights reserved 1522-8002/09/$25.00 DOI 10.1593/neo.81352
PY - 2009/2
Y1 - 2009/2
N2 - The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.
AB - The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.
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U2 - 10.1593/neo.81352
DO - 10.1593/neo.81352
M3 - Article
C2 - 19177203
AN - SCOPUS:61349137623
VL - 11
SP - 187
EP - 195
JO - Neoplasia (United States)
JF - Neoplasia (United States)
SN - 1522-8002
IS - 2
ER -