title: Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer.
abstract: OBJECTIVE
  To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay).
  
  
  RESULTS
  Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients.
  
  
  CONCLUSIONS
  Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.
authors.affiliation: US Oncology, Baylor University Medical Center, Dallas, TX, USA. j.nemunaitis@usoncology.com
authors.forename: J
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: S G
authors.initials: SG
authors.lastname: Swisher
authors.forename: T
authors.initials: T
authors.lastname: Timmons
authors.forename: D
authors.initials: D
authors.lastname: Connors
authors.forename: M
authors.initials: M
authors.lastname: Mack
authors.forename: L
authors.initials: L
authors.lastname: Doerksen
authors.forename: D
authors.initials: D
authors.lastname: Weill
authors.forename: J
authors.initials: J
authors.lastname: Wait
authors.forename: D D
authors.initials: DD
authors.lastname: Lawrence
authors.forename: B L
authors.initials: BL
authors.lastname: Kemp
authors.forename: F
authors.initials: F
authors.lastname: Fossella
authors.forename: B S
authors.initials: BS
authors.lastname: Glisson
authors.forename: W K
authors.initials: WK
authors.lastname: Hong
authors.forename: F R
authors.initials: FR
authors.lastname: Khuri
authors.forename: J M
authors.initials: JM
authors.lastname: Kurie
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: D M
authors.initials: DM
authors.lastname: Nguyen
authors.forename: J C
authors.initials: JC
authors.lastname: Nesbitt
authors.forename: R
authors.initials: R
authors.lastname: Perez-Soler
authors.forename: K M
authors.initials: KM
authors.lastname: Pisters
authors.forename: J B
authors.initials: JB
authors.lastname: Putnam
authors.forename: W R
authors.initials: WR
authors.lastname: Richli
authors.forename: D M
authors.initials: DM
authors.lastname: Shin
authors.forename: G L
authors.initials: GL
authors.lastname: Walsh
authors.forename: J
authors.initials: J
authors.lastname: Merritt
authors.forename: J
authors.initials: J
authors.lastname: Roth
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects; D016158:Genes, p53; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D015552:Injections, Intralesional; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity / Q000235:genetics; D013194:Staining and Labeling
chemical_list: D000914:Antibodies, Viral; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D002945:Cisplatin