Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer.
BACKGROUND
Patients with recurrent ovarian cancer were treated with a replication-deficient recombinant adenovirus containing the herpes simplex virus thymidine kinase gene administered intraperitoneally (i.p.) followed by administration of an anti-herpetic prodrug and topotecan.


METHODS
A total of 10 patients with stage IIIc epithelial ovarian cancer underwent secondary debulking to < or =0.5 cm residual tumor. Patients with normal i.p. flow received i.p. delivery of adenovirus. Two patients each were treated on dose level 1 (2 x 10(10) vector particles (VP)), dose level 2 (2 x 10(11) VP), and dose level 3 (2 x 10(12) VP); four patients were treated on dose level 4 (2 x 10(13) VP). Acyclovir and topotecan were started 24 hours after vector delivery.


RESULTS
No patient treated at any dose level incurred unanticipated toxic effects, and all side effects resolved. The most common adverse event was myelosuppression: grade 3 or 4 thrombocytopenia with grade 2-4 anemia in three patients and grade 3 or 4 neutropenia in eight patients. Three patients developed thrombocytosis and three patients had a mild elevation of serum glutamic pyruvic transaminase/alanine aminotransferase. Temperature elevations that were not associated with detectable infection occurred in two patients.


CONCLUSIONS
I.p. delivery of adenoviral vector with concomitant topotecan chemotherapy was well tolerated without significant lasting toxicities. Side effects were independent of the dose of adenoviral vector.
Hasenburg
A
A
Department of Obstetrics and Gynecology, Freiburg University Medical Center, Germany.
Tong
X W
XW
Rojas-Martinez
A
A
Nyberg-Hoffman
C
C
Kieback
C C
CC
Kaplan
A
A
Kaufman
R H
RH
Ramzy
I
I
Aguilar-Cordova
E
E
Kieback
D G
DG
D000212:Acyclovir / Q000008:administration & dosage / Q000627:therapeutic use; D000230:Adenocarcinoma / Q000628:therapy; D018262:Adenocarcinoma, Clear Cell / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003131:Combined Modality Therapy; D018283:Cystadenocarcinoma, Papillary / Q000628:therapy; D004247:DNA / Q000032:analysis; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007274:Injections, Intraperitoneal; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000628:therapy*; D016133:Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000235:genetics*; D019772:Topotecan / Q000008:administration & dosage / Q000627:therapeutic use*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019772:Topotecan; D004247:DNA; D013937:Thymidine Kinase; D000212:Acyclovir