Recombinant E1-deleted adenovirus-mediated gene therapy for cancer: efficacy studies with p53 tumor suppressor gene and liver histology in tumor xenograft models.
Type 5 adenoviral (Ad) vectors have been the "vector-of-choice" for preclinical studies on p53 tumor suppressor gene therapy of cancer. Previous studies have examined the in vivo efficacy of p53 Ad when given intratumorally. However published information does little to guide clinicians in the design of intraperitoneal (i.p.) dosing trials for i.p. tumors, e.g., ovarian, or clinical trials using regional organ perfusion, e.g., for lung tumors. Therefore, we examined several parameters with special significance for these routes of administration. Lung metastases from p53mut MDA-MB-231 mammary xenografts were treated with therapeutic levels of intravenous buffer, beta-galactosidase (beta-Gal) Ad, or p53 Ad. Treatment with intravenous p53 Ad significantly reduced the number of metastases per lung and there was a dramatic reduction in the surface area occupied by these tumors as compared to control groups. Two types of i.p. tumor xenografts were used for preclinical modeling of i.p. gene therapy, the p53null SK-OV-3 ovarian and the p53mut DU-145 prostate human cancers. In a study examining the effect of different vehicle volumes on the efficacy of a constant drug dose, all mice treated with p53 Ad had reduced tumor burden compared to controls. Dosing volumes between 0.2 and 1 ml were equally effective and all were more effective than a dosing volume of 0.1 ml. However, reduced efficacy was observed when a volume of 1.5 ml was used. When the effect of dosing frequency on antitumor efficacy was examined, fractionated doses of p53 Ad had somewhat greater efficacy than fewer, bolus injections. One of the significant elements in the emerging toxicology associated with recombinant adenoviruses is the hepatocyte pathology caused by high systemic concentrations of adenovirus. For recombinant Ad used in this study, there was a pronounced dose-dependence for the liver response, with very high, repeated doses causing significant hepatocellular insult. Expression of cytoplasmic beta-Gal protein coincided with areas of greatest damage in mice treated with high doses of beta-Gal Ad. Ultrastructural examination of hepatocyte intranuclear inclusions revealed moderately electron-dense, tightly packed granular material interspersed with more electron-dense nuclear material. Human tumor xenografts, but not mouse tissues, expressed viral hexon protein. In summary, hepatic toxicity caused by high concentrations of recombinant adenovirus was observed in murine cancer models. However, therapeutic levels of p53 Ad could be achieved which had dramatic efficacy without significant pathology.
Nielsen
L L
LL
Tumor Biology Department, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Gurnani
M
M
Syed
J
J
Dell
J
J
Hartman
B
B
Cartwright
M
M
Johnson
R C
RC
D000256:Adenoviridae / Q000235:genetics*; D017498:Adenovirus E1 Proteins / Q000235:genetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary / Q000628:therapy; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy; D011471:Prostatic Neoplasms / Q000628:therapy; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics
D017498:Adenovirus E1 Proteins; D001616:beta-Galactosidase