TY - JOUR
T1 - A novel red fluorescent protein orthotopic pancreatic cancer model for the preclinical evaluation of chemotherapeutics
AU - Katz, Matthew H.
AU - Takimoto, Shinako
AU - Spivack, Daniel
AU - Moossa, A. R.
AU - Hoffman, Robert M.
AU - Bouvet, Michael
N1 - Funding Information:
This study was supported in part by the Department of Health Services, California Cancer Research Program (Grant 97-120B), and US National Cancer Institute Grants P30 CA 23100-1851 and R43-89779.
PY - 2003/7
Y1 - 2003/7
N2 - Background. Realistic models of pancreatic cancer are necessary to develop effective drugs for the disease. More aggressive tumor models enhanced by brighter fluorescent biomarkers to follow the disease in real time would enhance the ability to predict accurately the effect of novel therapeutics on this particularly malignant human cancer. Materials and methods. A novel, highly fluorescent, red fluorescent protein (RFP)-expressing pancreatic cancer model was orthotopically established in nude mice. The MIA-PaCa-2 human pancreatic cancer cell line was transduced with RFP and grown subcutaneously. Fluorescent tumor fragments were then surgically transplanted onto the nude mouse pancreas. Groups treated with intraperitoneal gemcitabine or intravenous irinotecan were sequentially imaged to compare, in real time, the antimetastatic and antitumor effects of these agents compared with untreated controls. Results. Rapid tumor growth and widespread metastases developed in untreated mice within 2 weeks, leading to a median survival of 21 days. In contrast, significant tumor growth suppression and consequent increase in survival (32.5 days, P = 0.009) were achieved with CPT-11. Gemcitabine highly improved survival (72 days, P = 0.004) by inducing transient tumor regression over the first 3 weeks. However, at this time, growth and dissemination occurred despite continued treatment, suggesting the development of tumor resistance. The antimetastatic efficacy of each drug was followed noninvasively in real time by imaging the RFP-expressing tumor and metastases, and was confirmed by fluorescent open imaging of autopsy specimens. Conclusions. This highly metastatic model reliably simulates the aggressive course of human pancreatic cancer. Noninvasive, sequential imaging permits quantification of tumor growth and dissemination and, thereby, real time evaluation of therapeutic efficacy. These features make this model an ideal, preclinical system with which to study novel therapeutics for pancreatic cancer.
AB - Background. Realistic models of pancreatic cancer are necessary to develop effective drugs for the disease. More aggressive tumor models enhanced by brighter fluorescent biomarkers to follow the disease in real time would enhance the ability to predict accurately the effect of novel therapeutics on this particularly malignant human cancer. Materials and methods. A novel, highly fluorescent, red fluorescent protein (RFP)-expressing pancreatic cancer model was orthotopically established in nude mice. The MIA-PaCa-2 human pancreatic cancer cell line was transduced with RFP and grown subcutaneously. Fluorescent tumor fragments were then surgically transplanted onto the nude mouse pancreas. Groups treated with intraperitoneal gemcitabine or intravenous irinotecan were sequentially imaged to compare, in real time, the antimetastatic and antitumor effects of these agents compared with untreated controls. Results. Rapid tumor growth and widespread metastases developed in untreated mice within 2 weeks, leading to a median survival of 21 days. In contrast, significant tumor growth suppression and consequent increase in survival (32.5 days, P = 0.009) were achieved with CPT-11. Gemcitabine highly improved survival (72 days, P = 0.004) by inducing transient tumor regression over the first 3 weeks. However, at this time, growth and dissemination occurred despite continued treatment, suggesting the development of tumor resistance. The antimetastatic efficacy of each drug was followed noninvasively in real time by imaging the RFP-expressing tumor and metastases, and was confirmed by fluorescent open imaging of autopsy specimens. Conclusions. This highly metastatic model reliably simulates the aggressive course of human pancreatic cancer. Noninvasive, sequential imaging permits quantification of tumor growth and dissemination and, thereby, real time evaluation of therapeutic efficacy. These features make this model an ideal, preclinical system with which to study novel therapeutics for pancreatic cancer.
KW - Gemcitabine
KW - Irinotecan
KW - Orthotopic mouse model
KW - Pancreatic cancer
KW - Red fluorescent protein
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U2 - 10.1016/S0022-4804(03)00234-8
DO - 10.1016/S0022-4804(03)00234-8
M3 - Article
C2 - 12943825
AN - SCOPUS:0041734667
SN - 0022-4804
VL - 113
SP - 151
EP - 160
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -