Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: Results of a phase I clinical trial

Max W. Sung, Hsu Chong Yeh, Swan N. Thung, Myron E. Schwartz, John P. Mandeli, Shu Hsia Chen, Savio L.C. Woo

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

Animal studies have shown that direct injection of an adenoviral vector (Adv.RSV-tk) expressing the herpes thymidine kinase gene into established tumors in the liver, followed by systemic ganciclovir administration, was effective in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I trial in patients with metastatic colorectal adenocarcinoma in the liver to assess the safety of intratumoral Adv.RSV-tk injection (escalating doses) followed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous needle placement with concurrent ultrasonographic monitoring to prevent injection or leakage into adjacent normal liver structures. We treated 16 patients in five dose level cohorts of Adv.RSV-tk, from 1.0 × 1010 to 1.0 × 1013 virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients. These results indicate that Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases at doses up to 1.0 × 1013 virus particles per patient, and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.

Original languageEnglish (US)
Pages (from-to)182-191
Number of pages10
JournalMolecular Therapy
Volume4
Issue number3
DOIs
StatePublished - 2001

Keywords

  • Adenovirus
  • Colorectal cancer
  • Ganciclovir
  • Gene therapy
  • Herpes simplex
  • Liver
  • Thymidine kinase
  • Ultrasonography

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: Results of a phase I clinical trial'. Together they form a unique fingerprint.

Cite this