Enhancement of antitumor effect by intratumoral administration of bax gene in combination with anticancer drugs in gastric cancer.
Proapototic gene is an important target to enhance the chemotherapeutic effect in cancer cells. Based on in vitro study showing that the introduction of bax gene enhanced the sensitivity to anticancer drugs, we examined whether the intratumoral administration of bax gene could enhance the anti-tumor effect in combination with anticancer drugs in gastric cancer. The human gastric cancer cell line, MKN45 was transplanted into nude mice, and the intratumoral administration of bax gene was performed using the bax cDNA plasmid complexed with a cationic lipopolyamine. The enhancement of antitumor effect was examined in the combination with 5-fluorouracil (5-FU) and cisplatin (CDDP). The anticancer drugs were administered intraperitoneally with one third of LD50 four times at 4-day intervals, and the antitumor effect was assessed by the NCI protocol. The expression of bax gene was analyzed by RT-PCR and the apoptotic cell death was assessed by TUNEL method. The intratumoral administration of bax gene alone showed slight anti-tumor effect as compared to that of control tumor injected with vector alone. The antitumor effect of 5-FU and CDDP was significantly enhanced in the combination with intra-tumoral administration of bax gene as compared to that of CDDP and 5-FU alone (p<0.05, Student's t-test). The enhancement of antitumor effect was associated with the constitutive overexpression of bax gene and with the induction of apoptosis in the tumor treated with anticancer drug and bax gene. These results indicate that the combination therapy of intratumoral administration of bax gene complexed with a cationic lipopolyamine and anticancer drugs may provide us a new strategy for cancer chemotherapy to enhance its therapeutic efficacy in gastric cancer as termed with gene-chemotherapy.
Kim
R
R
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. rkim@ipc.hiroshima-u.ac.jp
Minami
K
K
Nishimoto
N
N
Toge
T
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002411:Cation Exchange Resins / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D000077143:Docetaxel; D005472:Fluorouracil / Q000008:administration & dosage; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007202:Indicators and Reagents / Q000627:therapeutic use; D008055:Lipids / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013274:Stomach Neoplasms / Q000188:drug therapy*; D043823:Taxoids; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D002411:Cation Exchange Resins; D007202:Indicators and Reagents; D008055:Lipids; C086724:Lipofectamine; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D051028:bcl-2-Associated X Protein; D000077143:Docetaxel; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil