Treatment of peritoneal carcinomatosis with intraperitoneal administration of Ad-hARF.
BACKGROUND
Peritoneal dissemination of cancer is a terminal condition with limited therapeutic options. Because the peritoneal cavity is a single enclosed space, regional treatment approaches for isolated peritoneal cancrinomatosis are appealing. There is a potential role for gene therapy in the management of peritoneal cancrinomatosis.


METHODS
An adenoviral construct of the human p14ARF gene (a tumor suppressor) and a 22 amino acid sequence of the ARF gene product, which has cell membrane penetrating properties, were assayed for proapoptotic properties in a human colorectal cancer cell line (Clone A) cells in vitro. Peritoneal carcinomatosis derived from Clone A cells was also established in nude mice and then treated with intraperitoneal administration of an adenoviral construct of the human p14ARF gene.


RESULTS
Treatment of ARF-negative Clone A cells with Ad-hARF in vitro reestablished ARF function. However, the cell penetrating ARF-related peptide did not restore ARF function in Clone A cells. Treatment of Clone A peritoneal xenografts with a single intraperitoneal dose of Ad-hARF (9 × 10(6) viral particles) suppressed the progression of peritoneal disease. Weekly (six times) administration of the Ad-hARF at a lower dose (3 × 10(6) viral particles) also suppressed tumor progression.


CONCLUSIONS
Treatment of peritoneal carcinomatosis by intraperitoneal administration of adenoviral constructs of inactivated tumor suppressor genes may be a feasible clinical approach, and ARF may represent a suitable molecular target for tumors where the ARF gene is inactivated.
Department of Surgery, University of Massachusetts Medical School, Worcester, MA. Electronic address: barur.rajeshkumar@umassmed.edu.
Barur R
BR
Rajeshkumar
Department of Surgery, University of Massachusetts Medical School, Worcester, MA; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
Seema
S
Paliwal
Department of Surgery, University of Massachusetts Medical School, Worcester, MA.
Laura
L
Lambert
Division of Hematology, Oncology, and Palliative Care and VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA.
Steven R
SR
Grossman
Department of Surgery, University of Massachusetts Medical School, Worcester, MA; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
Giles F
GF
Whalen
D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D019942:Genes, p16; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary* / Q000628:therapy*; D011897:Random Allocation; D016896:Treatment Outcome; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D025803:Tumor Suppressor Protein p14ARF
ARF tumor suppressor; Adenoviral-mediated gene therapy; Colon cancer; Peritoneal carcinomatosis