Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.
OBJECTIVE
Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial.


METHODS
An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12).


RESULTS
E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites.


CONCLUSIONS
These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.
Hortobagyi
G N
GN
Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. ghorto@notes.mdacc.tmc.edu
Ueno
N T
NT
Xia
W
W
Zhang
S
S
Wolf
J K
JK
Putnam
J B
JB
Weiden
P L
PL
Willey
J S
JS
Carey
M
M
Branham
D L
DL
Payne
J Y
JY
Tucker
S D
SD
Bartholomeusz
C
C
Kilbourn
R G
RG
De Jager
R L
RL
Sneige
N
N
Katz
R L
RL
Anklesaria
P
P
Ibrahim
N K
NK
Murray
J L
JL
Theriault
R L
RL
Valero
V
V
Gershenson
D M
DM
Bevers
M W
MW
Huang
L
L
Lopez-Berestein
G
G
Hung
M C
MC
D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000328:Adult; D000368:Aged; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002784:Cholesterol / Q000031:analogs & derivatives; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D022761:Gene Transfer, Horizontal; D018734:Genes, erbB-2; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007267:Injections; D019394:Ki-67 Antigen; D008081:Liposomes; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010529:Peritoneal Cavity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013909:Thorax; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; D016207:Cytokines; D019394:Ki-67 Antigen; D008081:Liposomes; C070648:3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol; D002784:Cholesterol