Coexpression of a multidrug resistance gene (MDR1) and herpes simplex virus thymidine kinase gene in a bicistronic retroviral vector Ha-MDR-IRES-TK allows selective killing of MDR1-transduced human tumors transplanted in nude mice.
Ha-MDR-IRES-TK is a bicistronic vector that coexpresses the MDR1 gene and the herpes simplex virus thymidine kinase (HSV-TK) gene. In the present study we examined the effect of ganciclovir on MDR1-positive tumors that have been transduced with Ha-MDR-IRES-TK. To establish a human tumor xenograft model of MDR1-transduced recurrent tumors, human KB-3-1 carcinoma cells were transduced with HaMDR or Ha-MDR-IRES-TK, and one each of representative clones, termed KB/MDR and KB/MDR-TK, respectively, were isolated. KB/MDR and KB/MDR-TK showed similar levels of multidrug resistance in vitro. Vinblastine strongly inhibited the growth of the parental KB-3-1 tumors in nude mice but showed little or no effect against KB/MDR-TK tumors. Ganciclovir inhibited the in vivo growth of KB/MDR-TK tumors almost completely under conditions that did not affect the growth of KB-3-1 tumors. Coadministration of vinblastine and ganciclovir inhibited the in vivo growth of KB/MDR-TK premixed with KB-3-1 at any ratio. Long-term, high-level expression of human P-glycoprotein was observed in peripheral blood cells of mice transplanted with Ha-MDR-IRES-TK-transduced bone marrow cells. Ganciclovir eliminated the P-glycoprotein-positive normal blood cells. However, no systemic toxicity was observed. These results clearly demonstrate that it is possible to use ganciclovir to treat MDR1-positive tumors that have been unintentionally transduced with Ha-MDR-IRES-TK. This safety-modified vector should be useful for introducing the MDR1 gene into bone marrow cells to protect normal cells from the toxic effects of cancer chemotherapy.
Sugimoto
Y
Y
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Sato
S
S
Tsukahara
S
S
Suzuki
M
M
Okochi
E
E
Gottesman
M M
MM
Pastan
I
I
Tsuruo
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells; D015774:Ganciclovir / Q000627:therapeutic use; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012190:Retroviridae / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000627:therapeutic use
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014747:Vinblastine; D013937:Thymidine Kinase; D015774:Ganciclovir