[Application of bioinformatics analysis to optimize amifostine combination therapeutic regimen of myelodysplastic syndrome].
OBJECTIVE
To apply bioinformatics analysis to study the potential mechanism of amifostine for the treatment of myelodysplastic syndrome (MDS) and optimize amifostine combination regimen to further improve the efficacy and prognosis of MDS.


METHODS
Bioinformatics analysis: Internet-based human gene expression open database was used to predict the genomic profiling by regulation of amifostine and gene expression of MDS. And then possible target genes of amifostine were screened to predict the feasibility of amifostine combination regimen. Finally, similar analysis of gene expression profiling was conducted to forecast the potential therapeutic drugs for MDS. Clinical investigation: eighteen patients with MDS, non-responding to traditional drugs, were enrolled. According to the latest WHO classification, the patients were divided into 7 patients of refractory anemia (RA), 2 patients of refractory anemia with ring sideroblast (RARS) and 9 patients of refractory cytopenia with multilineage dysplasia (RCMD). Distributions of age was 19-91 years old (mean: 79). There were 17 males and 1 female. The regimen of amifostine plus recombinant human erythropoietin (rhEPO) was used to treat the MDS patients. Administration formula was as follows: the intravenous drip of amifostine at a dosage of 0.4 gram per day was given 5 days weekly for 4 consecutive weeks; the subcutaneous injection of rhEPO at a dosage of 6 000 IU was given 3 times weekly. Therapeutic effect was evaluated 2 weeks post-therapy.


RESULTS
Approximately 2.6 percent of human gene involved in apoptosis, cell cycle and differentiation was regulated by amifostine. Especially, upregulation of ELK1 expression, which belongs to downstream functional gene of EPO pathway, and downregulation of Cyclin D1 expression were successfully predicted. Based on the potential therapeutic mechanism amifostine for MDS, amifostine plus EPO had dual effects on MDS, i. e. promotion of hematopoiesis and inhibition of tumor cell proliferation. Clinical investigation showed that the response rates of hemoglobin, neutrophil and platelet were 83.3%, 66.7% and 55.6% respectively. The results suggested that the regimen of amifostine plus EPO had better therapeutic effects than a single agent.


CONCLUSIONS
The study successfully used bioinformatics analysis to screen target genes regulated by amifostine and optimize amifostine combination therapeutic regimen for MDS. Bioinformatics method is a convenient, economical and effective supplementary approach for studying the pathogenesis and therapeutics of MDS.
Lu
Xue-Chun
XC
Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China. luxuechun@126.com
Yang
Bo
B
Zhu
Hong-Li
HL
Fan
Hui
H
Li
Su-Xia
SX
Liu
Yang
Y
Yao
Shan-Qian
SQ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004999:Amifostine / Q000008:administration & dosage* / Q000627:therapeutic use; D019295:Computational Biology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
D004999:Amifostine