Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER)
| Autor: | Douglas J. Francis, Colin N. Chesterman, Paula T. Hammond, Jason Z. Deng, Levon M. Khachigian, Diona L. Damian, Ross StC Barnetson, Carlos China, Fergal J. Moloney, Benafsha Yosufi, Eun-Ae Cho, Stephen W. Morton, Gary M. Halliday, Mark J. Raftery, Hendrik-Tobias Arkenau, Annie Au-Yeung, Richard A. Scolyer, Hong Cai |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Deng, Jason Z., Morton, Stephen Winford, Hammond, Paula T. |
| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty Pathology Skin Neoplasms Maximum Tolerated Dose Angiogenesis Antineoplastic Agents Injections Intralesional medicine.disease_cause Gastroenterology Immune system Internal medicine Biopsy Carcinoma Medicine Humans Adverse effect medicine.diagnostic_test business.industry General Medicine DNA Catalytic Middle Aged medicine.disease Treatment Outcome Tolerability Carcinoma Basal Cell Female business Carcinogenesis Dz13 |
| Zdroj: | PMC |
| ISSN: | 1474-547X |
| Popis: | 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. Findings 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. Interpretation Dz13 was safe and well tolerated after single intratumoral injections at all doses. Cancer Institute NSW Cancer Council Australia National Health and Medical Research Council (Australia) |
| Databáze: | OpenAIRE |
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