title: Significant antitumor activity of cationic multilamellar liposomes containing human interferon-beta gene in combination with 5-fluorouracil against human renal cell carcinoma.
abstract: Immunotherapy is one of the most effective treatments against metastatic renal cell carcinoma (RCC). However, the response rate is not high. Therefore, more effective therapies are necessary for patients with metastatic RCC. We previously reported on the significant antitumor activity of cationic multilamellar liposome containing human interferon-beta (huIFN-beta) gene (IAB-1) against RCC. We then examined the antitumor effect of IAB-1 in combination with anticancer drugs against RCC. The cytotoxicity of IAB-1 alone, and in combination with anticancer drugs, cisplatin, adriamycin, 5-fluorouracil, gemcitabine, paclitaxel and irinotecan hydrochloride against the human RCC cell line NC65 was examined by the colorimetric method using tetrazolium salt. For the in vivo study, we used NC65 cells inoculated into the severe combined immunodeficiency mouse. The results showed that the in vitro combination therapy with IAB-1 and 5-FU was more cytotoxic than IAB-1 alone. However, synergistic cytotoxicity was not observed when combined with IAB-1 and other anticancer drugs. NC65 tumors transfected with IAB-1 in mice were smaller than those receiving an injection of empty liposome or the recombinant huIFN-beta protein. Treatment with IAB-1 in combination with 5-FU resulted in significant anticancer activity. IAB-1 enhanced the activity of thymidine phosphorylase (TP), which converts 5-FU to the active metabolite, FdUMP. In contrast, IAB-1 decreased the activity of thymidylate synthase (TS), which is a target enzyme of 5-FU. In conclusion, these findings indicate that a combination of IAB-1 and 5-FU may have enhanced antitumor activity against human RCC, suggesting its potential clinical application. The mechanism of enhanced cytotoxicity by combination therapy with IAB-1 and 5-FU may up-regulate TP activity and down-regulate TS activity.
authors.affiliation: Department of Urology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizutani
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Jun
authors.initials: J
authors.lastname: Fujiwara
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ishida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Toiyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Abe
authors.forename: Issei
authors.initials: I
authors.lastname: Hayashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Okada
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawauchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mizuno
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshida
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002412:Cations; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016899:Interferon-beta / Q000008:administration & dosage* / Q000235:genetics; D000077146:Irinotecan; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008081:Liposomes; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000008:administration & dosage; D013939:Thymidine Phosphorylase / Q000187:drug effects / Q000378:metabolism; D013940:Thymidylate Synthase / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D002412:Cations; D008081:Liposomes; D003841:Deoxycytidine; D000077146:Irinotecan; D016899:Interferon-beta; D004317:Doxorubicin; D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil; D002166:Camptothecin; D000093542:Gemcitabine