Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.
BACKGROUND
Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments.


METHODS
Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU.


RESULTS
Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression.


CONCLUSIONS
Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D001999:Bronchoscopy; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004279:DNA, Viral / Q000302:isolation & purification; D018450:Disease Progression; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000009:adverse effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D016019:Survival Analysis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome