Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growth.
Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene-directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs (HB1.F3.CD or HB1.F3.CE cells) engineered to express a suicide gene (CD or CE) selectively migrated toward ovarian cancer cells. A [(3)H] thymidine incorporation assay was conducted to measure the proliferative index. Treatment of human epithelial ovarian cancer cell line (SKOV-3, an ovarian adenocarcinoma derived from the ascites of an ovarian cancer patient) with the prodrugs 5-fluorocytosine (5-FC) or camptothecin-11 (CPT-11) in the presence of HB1.F3.CD or HB1.F3.CE cells resulted in the inhibition of ovarian cancer cell growth. Based on the data presented herein, we suggest that GESTECs expressing CD/CE may have a potent advantage to selectively treat ovarian cancers.
Kim
Ki-Yon
KY
Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Kim
Seung U
SU
Leung
Peter C K
PC
Jeung
Eui-Bae
EB
Choi
Kyung-Chul
KC
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D005260:Female; D005437:Flucytosine / Q000378:metabolism / Q000494:pharmacology*; D041722:Genes, Transgenic, Suicide; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D010051:Ovarian Neoplasms / Q000628:therapy*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D013234:Stem Cells
D000963:Antimetabolites; D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D005437:Flucytosine; D043525:Cytosine Deaminase; D002166:Camptothecin