Isolated hepatic perfusion with high-dose melphalan results in immediate alterations in tumor gene expression in patients with metastatic ocular melanoma.
BACKGROUND
Patients with ocular melanoma liver metastases have a poor prognosis, treatment options are limited, and median survival is less than 1 year. In this study, we characterized the early molecular changes that occur in tumors immediately after vascular isolation perfusion with melphalan with hyperthermia in patients with hepatic metastases from ocular melanoma.


METHODS
Patients underwent treatment on a clinical trial using a 60-min hyperthermic isolated hepatic perfusion (IHP) with melphalan. Microarray analysis was performed in 28 tumor samples obtained intraoperatively of which 12 were pre- and 16 were post-IHP. Various statistical analyses were performed to identify differentially expressed genes and gene categories between the groups.


RESULTS
Median survival of 17 treated patients was 11.9 months. Unsupervised hierarchical clustering of all tumors resulted in separation of pre and post-IHP samples into two distinct groups. Analysis of genes showed that the Ras GTPase activator, ecotropic viral integration site 5 (EVI5), and several other melanoma-associated genes were overexpressed in pre-IHP tumors. In post-IHP samples the overexpression of a DNA replication associated gene, replication factor C (RFC5), was significantly associated with shortened survival (P < 0.003). Other major gene ontology categories identified in the post-IHP tumor samples were DNA-directed RNA polymerase activity and chromatin remodeling, both important categories involved in DNA replication and repair.


CONCLUSIONS
These results demonstrate that acute changes in gene expression patterns occur in tumors immediately after treatment with melphalan administered via hyperthermic IHP. Rapid activation of DNA synthesis and repair pathways may be a mechanism of acquired tumor resistance in patients with ocular melanoma.
Varghese
Sheelu
S
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
Xu
Hui
H
Bartlett
David
D
Hughes
Marybeth
M
Pingpank
James F
JF
Beresnev
Tatiana
T
Alexander
H Richard
HR
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D014408:Biomarkers, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D015331:Cohort Studies; D005134:Eye Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006979:Hyperthermia, Induced; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D008558:Melphalan