Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors.
p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector containing wt p53 was carried out in patients with metastatic melanoma or breast cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by reverse transcriptase-polymerase chain reaction in tumor tissue. A total of six (five melanoma and one breast adenocarcinoma) patients were treated at dose levels dependent upon tumor size/dose escalation sequence. Five of six patients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injection were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose. p53 gene therapy by i.t. injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.
Department of Dermatology, University Hospital of Zürich, Switzerland. dummer@derm.unizh.ch
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R
Dummer
J
J
Bergh
Y
Y
Karlsson
J A
JA
Horowitz
N H
NH
Mulder
Huinink DTB
G
G
Burg
G
G
Hofbauer
S
S
Osanto
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000032:analysis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D003673:Defective Viruses; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D008875:Middle Aged; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012449:Safety; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014162:Transfection; D017201:Virus Shedding
D000914:Antibodies, Viral; D012333:RNA, Messenger