title: Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER).
abstract: BACKGROUND
  The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings.
  
  
  METHODS
  Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 μg Dz13, in a 50 μL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers.
  
  
  RESULTS
  Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated.
  
  
  CONCLUSIONS
  Dz13 was safe and well tolerated after single intratumoral injections at all doses.
  
  
  BACKGROUND
  Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council.
authors: Dermatology, Sydney Medical School, Bosch Institute, Royal Prince Alfred Hospital at University of Sydney, Sydney, NSW, Australia.
authors: Eun-Ae
authors: EA
authors: Cho
authors: Fergal J
authors: FJ
authors: Moloney
authors: Hong
authors: H
authors: Cai
authors: Annie
authors: A
authors: Au-Yeung
authors: Carlos
authors: C
authors: China
authors: Richard A
authors: RA
authors: Scolyer
authors: Benafsha
authors: B
authors: Yosufi
authors: Mark J
authors: MJ
authors: Raftery
authors: Jason Z
authors: JZ
authors: Deng
authors: Stephen W
authors: SW
authors: Morton
authors: Paula T
authors: PT
authors: Hammond
authors: Hendrik-Tobias
authors: HT
authors: Arkenau
authors: Diona L
authors: DL
authors: Damian
authors: Douglas J
authors: DJ
authors: Francis
authors: Colin N
authors: CN
authors: Chesterman
authors: Ross St C
authors: RS
authors: Barnetson
authors: Gary M
authors: GM
authors: Halliday
authors: Levon M
authors: LM
authors: Khachigian
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021881:DNA, Catalytic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D021881:DNA, Catalytic; C485475:Dz13 DNAzyme
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