Early effects of FOLFOX treatment of colorectal tumour in an animal model: assessment of changes in gene expression and FDG kinetics.
OBJECTIVE
The very early chemotherapeutic effects of the FOLFOX (fluorouracil, folinic acid, oxaliplatin) protocol were assessed in mice implanted with a human colorectal cell line. The aim of this study was to identify changes in gene expression patterns and to detect combinations of PET parameters that may be helpful in identifying treated tumours early after chemotherapy using dynamic PET studies.


METHODS
A human colorectal cell line (HCT 116) was used in nude mice. Dynamic PET studies were performed in untreated (n = 13) and treated (n = 12) animals. The data were assessed using compartmental and noncompartmental analysis. The removed tumour specimens were assessed by gene array analysis to obtain quantitative information on gene expression.


RESULTS
One chemotherapeutic treatment using the FOLFOX protocol resulted in an upregulation of 2,078 gene probes by more than 25%, while 2,254 probes were downregulated following treatment. The gene array data demonstrated primarily an enhancement of genes related to apoptosis. In particular, the apoptosis antigen 1 (APO-1), p21 and the G protein-coupled receptor 87 (G-87) were 2.6- to 3.3-fold upregulated as compared to the expression in untreated animals. There was a 100% separation of untreated and treated animals on the basis of these three genes. The SUV and the FDG kinetic parameters obtained by compartmental and noncompartmental fitting were not significantly different when individual parameters were compared between groups. However, classification analysis of the combination of the PET parameters VB, K1, k3, and influx revealed an overall accuracy of 84%. We were able to identify 91.7% (11/12) of the treated animals and 76.9% (10/13) of the untreated animals correctly using the classification analysis of PET data.


CONCLUSIONS
Even one chemotherapeutic treatment using FOLFOX has an impact on gene expression and significantly modulates FDG kinetics. Quantitative assessment of the tracer kinetics and the application of classification analysis to the data are promising tools to identify those tumours that demonstrate a chemotherapeutic effect very early following treatment.
Strauss
Ludwig G
LG
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany. lgs@ads-lgs.de
Hoffend
Johannes
J
Koczan
Dirk
D
Pan
Leyun
L
Haberkorn
Uwe
U
Dimitrakopoulou-Strauss
Antonia
A
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D002955:Leucovorin / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D049268:Positron-Emission Tomography
D009944:Organoplatinum Compounds; D019788:Fluorodeoxyglucose F18; D002955:Leucovorin; D005472:Fluorouracil