Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation.
BACKGROUND
Hematopoietic stem cell transplantation is a curative treatment for several haematological malignancies. However, treatment related morbidity and mortality still is a limiting factor. Cyclophosphamide is widely used in condition regimens either in combination with other chemotherapy or with total body irradiation.


METHODS
We present the gene expression profile during cyclophosphamide treatment in 11 patients conditioned with cyclophosphamide for 2 days followed by total body irradiation prior to hematopoietic stem cell transplantation. 299 genes were identified as specific for cyclophosphamide treatment and were arranged into 4 clusters highly down-regulated genes, highly up-regulated genes, early up-regulated but later normalized genes and moderately up-regulated genes.


RESULTS
Cyclophosphamide treatment down-regulated expression of several genes mapped to immune/autoimmune activation and graft rejection including CD3, CD28, CTLA4, MHC II, PRF1, GZMB and IL-2R, and up-regulated immune-related receptor genes, e.g. IL1R2, IL18R1, and FLT3. Moreover, a high and significant expression of ANGPTL1 and c-JUN genes was observed independent of cyclophosphamide treatment.


CONCLUSIONS
This is the first investigation to provide significant information about alterations in gene expression following cyclophosphamide treatment that may increase our understanding of the cyclophosphamide mechanism of action and hence, in part, avoid its toxicity. Furthermore, ANGPTL1 remained highly expressed throughout the treatment and, in contrast to several other alkylating agents, cyclophosphamide did not influence c-JUN expression.
Experimental Cancer Medicine (ECM), Clinical Research Centre (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
Ibrahim
I
El-Serafi
Experimental Cancer Medicine (ECM), Clinical Research Centre (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
Manuchehr
M
Abedi-Valugerdi
Experimental Cancer Medicine (ECM), Clinical Research Centre (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden ; Clinical Research Centre (Novum), Karolinska University Hospital-Huddinge, Stockholm, Sweden.
Zuzana
Z
Potácová
Experimental Cancer Medicine (ECM), Clinical Research Centre (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden ; Department of Genetics, Royan Institute, Tehran, Iran.
Parvaneh
P
Afsharian
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital-Huddinge, Stockholm, Sweden ; Department of Therapeutic Immunology, Karolinska Institute, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Jonas
J
Mattsson
Cancer Centre of Karolinska (CCK), Department of Oncology-Pathology, Karolinska Institutet, Solna, Stockholm, Sweden.
Ali
A
Moshfegh
Experimental Cancer Medicine (ECM), Clinical Research Centre (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden ; Clinical Research Centre (Novum), Karolinska University Hospital-Huddinge, Stockholm, Sweden.
Moustapha
M
Hassan
D000293:Adolescent; D000328:Adult; D002648:Child; D016000:Cluster Analysis; D003520:Cyclophosphamide / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D059467:Transcriptome; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014916:Whole-Body Irradiation; D055815:Young Adult
D003520:Cyclophosphamide