Significant antitumor activity of cationic multilamellar liposomes containing human interferon-beta gene in combination with 5-fluorouracil against human renal cell carcinoma.
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.
Yamamoto
Kosuke
K
Department of Urology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Mizutani
Yoichi
Y
Nakanishi
Hiroyuki
H
Fujiwara
Jun
J
Ishida
Hirokazu
H
Toiyama
Daisuke
D
Abe
Koichi
K
Hayashi
Issei
I
Okada
Koichi
K
Kawauchi
Akihiro
A
Mizuno
Masaaki
M
Yoshida
Jun
J
Miki
Tsuneharu
T
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
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