Antitumor activity and reporter gene transfer into rat brain neoplasms inoculated with herpes simplex virus vectors defective in thymidine kinase or ribonucleotide reductase.
Herpes simplex virus (HSV) mutants or recombinant vectors might be useful oncolytic agents. Three general types of HSV vectors can be potentially used for this purpose: (1) mutants in viral transcription factors, such as ICP0 and ICP4; (2) mutants in enzymes involved in nucleic acid metabolism, such as thymidine kinase (TK) and ribonucleotide reductase (RR); and (3) mutants in neurovirulence factors, such as gamma 34.5. We tested the destructive ability of each type against rat 9L gliosarcoma cells in culture. We found that the HSV vectors defective in TK or RR were more efficient at tumor cell lysis in culture than the other types of HSV vectors. This increased efficiency provided the rationale for evaluating the TK and RR mutants in vivo following their stereotactic inoculation into 9L gliosarcomas implanted in rat brains. We employed the X-gal enzymatic histochemical assay to show that HSV-mediated lacZ gene expression was present in cells within the tumor mass in a relatively selective fashion. Immunoreactive HSV capsid and core antigens were present both in cells within the tumor, as well as in cells such as neurons and astrocytes, directly adjacent to the tumor mass. Long-term survival studies revealed that rats treated with either the TK or RR mutant lived significantly longer than control rats (p = 0.014, Kruskal-Wallis one-way analysis of variance). These results indicate that HSV vectors, defective in enzymes needed in nucleic acid metabolism, can preferentially mediate lacZ gene expression in cells within the tumor. (ABSTRACT TRUNCATED AT 250 WORDS)
Boviatsis
E J
EJ
Department of Surgery (Neurosurgery Service) and Molecular, Harvard Medical School, Massachusetts General Hospital, Charlestown 02129, USA.
Scharf
J M
JM
Chase
M
M
Harrington
K
K
Kowall
N W
NW
Breakefield
X O
XO
Chiocca
E A
EA
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000628:therapy* / Q000821:virology; D016923:Cell Death; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D018316:Gliosarcoma / Q000201:enzymology / Q000628:therapy / Q000821:virology; D006651:Histocytochemistry; D007763:Lac Operon; D008297:Male; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D012264:Ribonucleotide Reductases / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism
D014764:Viral Proteins; D012264:Ribonucleotide Reductases; D013937:Thymidine Kinase