Histologic and immunohistochemical analysis of tissue response to adenovirus-mediated herpes simplex thymidine kinase gene therapy of ovarian cancer.
Herpes simplex virus (HSV) thymidine kinase (tk) gene incorporated into adenovirus was delivered intraperitoneally (ip) followed by an antiherpetic prodrug and topotecan in patients with recurrent epithelial ovarian cancer. Tissue response was evaluated. Ten patients underwent secondary debulking with subsequent delivery of ADV-HSV-tk therapy. Two patients each were treated at dose level 1 (2 x 10(10) vector particles = VP), 2 (2 x 10(11) VP), and 3 (2 x 10(12) VP); four patients were treated at dose level 4 (2 x 10(13) VP). Five patients underwent second-look surgery about one month after gene therapy (GT). Treatment response, presence of vector DNA, protein expression of steroid hormone receptors, p53, c-erbB2 and Ki67 protein were analyzed. At second-look, two out of five patients were tumor-free and none of their peritoneal biopsies showed vector DNA. After GT, the vital tumor mass was smaller, desmoplastic reaction had increased, and tumors were less differentiated with an increase of Ki67 expression. There was no change in expression of hormone receptors, p53, or c-erbB2. ADV-HSV-tk GT appears to eliminate cells with higher differentiation first and might induce fibrosis. Dedifferentiation might render residual cells more sensitive to chemotherapy secondary to their subsequent higher mitotic activity.
Hasenburg
A
A
Department of Obstetrics and Gynecology, Freiburg University Medical Center, Hugstetter Strasse 55, D-79106 Freiburg, Germany. ahasenb@frk.ukl.uni-freiburg.de
Fischer
D C
DC
Tong
X-W
XW
Rojas-Martinez
A
A
Nyberg-Hoffman
C
C
Orlowska-Volk
M
M
Kohlberger
P
P
Kaufman
R H
RH
Ramzy
I
I
Aguilar-Cordova
E
E
Kieback
D G
DG
D000260:Adenoviruses, Human / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D018283:Cystadenocarcinoma, Papillary / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D017931:DNA Primers / Q000737:chemistry; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016133:Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D024162:Second-Look Surgery; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D019772:Topotecan / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D014408:Biomarkers, Tumor; D017931:DNA Primers; D004279:DNA, Viral; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D013937:Thymidine Kinase; D019772:Topotecan; D016159:Tumor Suppressor Protein p53