Development of a chemoresistant orthotopic human nonsmall cell lung carcinoma model in nude mice: analyses of tumor heterogenity in relation to the immunohistochemical levels of expression of cyclooxygenase-2, ornithine decarboxylase, lung-related resistance protein, prostaglandin E synthetase, and glutathione-S-transferase-alpha (GST)-alpha, GST-mu, and GST-pi.
BACKGROUND
Nonsmall cell lung carcinomas (NSCLCs) are associated with very dismal prognoses, and adjuvant chemotherapy, including irinotecan, taxanes, platin, and vinca alkaloid derivatives, offer patients only slight clinical benefits. Part of the chemoresistance of NSCLC results from the expression in NSCLC cells of a very large set of endogenous proteins, which antagonize chemotherapy-mediated attacks on these tumor cells.


METHODS
The authors set up an orthotopic model of a human NSCLC by grafting A549 cells into the lungs of nude mice. They tried treating these A549 NSCLC orthotopic xenograft-bearing nude mice on the basis of various chemotherapeutic protocols, including chronic administrations of taxol, oxaliplatin, and irinotecan. A cyclooxygenase-2 (COX-2) inhibitor (NS-398) also was assayed in combination with taxol. The immunohistochemical expression levels of COX-2, prostaglandin E synthetase (PGES), ornithine decarboxylase (ODC), the lung-related resistance protein (LRP), and glutathione-S-transferase-alpha (GST-alpha), GST-mu, and GST-pi were quantitatively determined by means of computer-assisted microscopy in control and drug-treated NSCLC orthotopic xenografts.


RESULTS
The orthotopic A549 xenograft model developed in 100% of the grafted mice, leading to brain metastases in approximately 61% mice and to liver metastases in approximately 40% of mice. The model was resistant to taxol and oxaliplatin and was only weakly sensitive to irinotecan. High levels of chemoresistant markers (i.e., COX-2, PGES, ODC, LRP, GST-alpha, GST-mu, and GST-pi) were observed in the nontreated A549 xenografts, although with dramatic variations in individual expression. Taxol and oxaliplatin significantly increased the levels of expression of COX-2, PGES, GST-mu, and GST-pi in a number of different experimental protocols.


CONCLUSIONS
The A549 orthotopic xenograft model could be used to evaluate investigational chemotherapeutic agents to identify drugs rapidly that are more active than the drugs currently in use in hospitals.
Mathieu
Anne
A
Pathology Laboratory, Erasmus University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Remmelink
Myriam
M
D'Haene
Nicky
N
Penant
Stanislas
S
Gaussin
Jean-François
JF
Van Ginckel
Rob
R
Darro
Francis
F
Kiss
Robert
R
Salmon
Isabelle
I
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D000077146:Irinotecan; D007527:Isoenzymes / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D009955:Ornithine Decarboxylase / Q000378:metabolism; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000008:administration & dosage; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D015996:Survival Rate; D014183:Transplantation, Heterologous; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism; D000099187:Major Vault Protein
D014408:Biomarkers, Tumor; D002166:Camptothecin; D051546:Cyclooxygenase 2; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D019746:Intramolecular Oxidoreductases; D000077146:Irinotecan; D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D009955:Ornithine Decarboxylase; D000077150:Oxaliplatin; D017239:Paclitaxel; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C496540:PTGS2 protein, human; C496556:GSTP1 protein, human; C496557:Gstp1 protein, mouse; C119995:glutathione S-transferase alpha