A proof of glutathione S-transferase-pi-related multidrug resistance by transfer of antisense gene to cancer cells and sense gene to bone marrow stem cell.
In order to directly prove the involvement of GST-pi in drug resistance, it's antisense gene was transduced into human colorectal cancer cell line which has been shown to express high level of GST-pi and the sensitivity of this cell line to anticancer drugs were assessed. The transfectant showed higher sensitivity to adriamycin (3.3-fold), Cisplatnum (2.3-fold), Melphalan (2.2-fold), Etoposode (2.2-fold) than the parental cell, while the sensitivity to vincristine, mitomicin C, 5-fluorouracil was unchanged by transfection. When the transfectant and parental cells were innoculated in nude mice and treated with adriamycin, a significant suppression of tumor growth was observed with the transfectant as compared to the parental cell. On the basis of this observation, we then transduced sense GST-pi gene into human bone marrow stem cells (CD34+ cells) to protect them from toxicity of anticancer drug. The gene transduced CD34+ cells formed more CFU-GM than nontransduced CD34+ cell in the presence of adriamycin (30 ng/ml). Thus, the autotransplantation of GST-pi gene transduced cell into cancer patients to protect the bone marrow from subsequent highdose chemotherapy is considered to be a new strategy for cancer gene therapy.
Niitsu
Y
Y
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
Takahashi
Y
Y
Ban
N
N
Takayama
T
T
Saito
T
T
Katahira
T
T
Umetsu
Y
Y
Nakajima
T
T
Ohi
M
M
Kuga
T
T
Sakamaki
S
S
Matsunaga
T
T
Hirayama
Y
Y
Kuroda
H
H
Homma
H
H
Kato
J
J
Kogawa
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D016375:Antisense Elements (Genetics); D003114:Colony-Forming Units Assay; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D003520:Cyclophosphamide / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000235:genetics* / Q000502:physiology*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014161:Transduction, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D016375:Antisense Elements (Genetics); D007527:Isoenzymes; D004317:Doxorubicin; D003520:Cyclophosphamide; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse