Serotype chimeric and fiber-mutated adenovirus Ad5/19p-HIT for targeting renal cancer and untargeting the liver.
Despite some advances, patients with advanced renal cell carcinoma (RCC) cannot usually be cured. Alteration of the natural tropism of adenoviruses may permit more specific gene transfer to target tissues. The aim of this study was to use novel targeting moieties for adenoviral gene therapy of RCC. Previous work in rats suggested that use of Ad5/19p (Ad5 capsid with Ad19p fiber) with kidney vascular targeting moieties HTTHREP (HTT), HITSLLS (HIT), and APASLYN (APA) placed into the fiber knob might be useful for targeting kidney vasculature. Therefore, we sought to investigate the utility of Ad5/19p variants for gene delivery to human RCC cell lines, clinical samples, and orthotopic murine models of metastatic RCC. Six different human RCC cell lines were infected but only Ad5/19p-HIT showed increased transduction, and only in one cell line. Thus, we analyzed human normal and cancerous kidney specimens fresh from patients, which might better mimic the three-dimensional architecture of clinical tumors and found that Ad5/19p-HIT showed transduction levels similar to Ad5. In mice, we found that intraperitoneal and intravenous Ad5/19p-HIT transduced tumors at levels comparable to Ad5, and that intratumoral Ad5/19p-HIT was superior to Ad5. Liver tropism was significantly reduced in comparison with Ad5. Improvements in tumor-to-liver transduction ratios suggested that Ad5/19p-HIT may be promising for systemic gene delivery to kidney tumors.
Diaconu
Iulia
I
Cancer Gene Therapy Group, Molecular Cancer Biology Program, Transplantation Laboratory, Haartman Institute, and Finnish Institute for Molecular Medicine, University of Helsinki, 00014 Helsinki, Finland.
Denby
Laura
L
Pesonen
Sari
S
Cerullo
Vincenzo
V
Bauerschmitz
Gerd J
GJ
Guse
Kilian
K
Rajecki
Maria
M
Dias
João D
JD
Taari
Kimmo
K
Kanerva
Anna
A
Baker
Andrew H
AH
Hemminki
Akseli
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007680:Kidney Neoplasms / Q000628:therapy*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D012703:Serotyping; D014161:Transduction, Genetic
D010455:Peptides