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.