P21 gene expression as an indicator for the activity of adenovirus-p53 gene therapy in non-small cell lung cancer patients.
Alterations in the tumor suppressor gene p53 lead to impaired cell cycle control, allowing for the development and growth of tumors. To restore a loss of p53 function, we performed a phase I study of intratumoral gene therapy with adenovirus expressing wild-type p53 in patients with non-small cell lung cancer carrying mutations in the p53 gene. Furthermore, in a phase II study, gene therapy was complemented with simultaneous cisplatin/vinorelbine treatment. Biopsies were obtained from all treated patients before and 24-48 hours after gene therapy to study changes in the expression of p53 target genes. We report here that in most of the cases, the target gene p21 was up-regulated, especially when injection of higher doses of p53-expressing adenovirus was combined with simultaneous chemotherapy, whereas Pig3, previously reported to be highly up-regulated by p53, generally did not show a clear increase. Interestingly, a clear p21 gene response was observed only in tumors showing stabilization or regression. We conclude that p21 appears to be up-regulated after adenovirus-mediated p53 gene transfer and is the most sensitive marker tested for biological response to gene therapy in the small cohort of non-small cell lung cancers that were studied.
Boulay
J L
JL
Division of Oncology, University Hospital of Basel, Switzerland.
Perruchoud
A P
AP
Reuter
J
J
Bolliger
C
C
Herrmann
R
R
Rochlitz
C
C
D000256:Adenoviridae / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007267:Injections / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008297:Male; D009026:Mortality; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077235:Vinorelbine; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics
D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C411296:TP53I3 protein, human; D014747:Vinblastine; D020741:rho GTP-Binding Proteins; D002945:Cisplatin; D000077235:Vinorelbine