RESUMEN
2'-Deoxy-2'-methylidenecytidine (DMDC) is a new 2'-deoxycytidine (dCyd) antimetabolite. The present study compared its antitumor activities with those of 2',2'-difluorodeoxy-cytidine (gemcitabine) in 15 human cancer xenograft models. DMDC was highly resistant to cytidine (Cyd) deaminase, which deaminates the dCyd analogues to inactive molecules, whereas gemcitabine was susceptible to the enzyme. Given p.o., high antitumor activity with therapeutic index of more than 10 was found with DMDC in 7 of 15 xenograft lines. In contrast, gemcitabine given i.v. or p.o. was highly effective in 4 of 15 human cancer xenograft lines. The antitumor spectrum of these compounds was quite different, although their molecular targets are reported to be similar. DMDC was highly effective in tumors with higher levels of Cyd deaminase activity, whereas it showed only slight activity in those with lower levels of Cyd deaminase. In contrast, gemcitabine appeared to be less effective in tumors with high levels of Cyd deaminase. We also investigated the correlation with the susceptibility to the two dCyd antimetabolites and dCyd kinase activity in tumors, but none was observed. Cyd deaminase activity was found to be high in tumor tissues from various types of human cancers thus far tested, such as colorectal cancer and non-small cell lung cancer. Such cancer types or individual patients who have tumors with high activity of the enzyme may be targets for DMDC therapy.
Asunto(s)
Antineoplásicos/metabolismo , Citidina Desaminasa/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Inhibidores Enzimáticos/metabolismo , Neoplasias/enzimología , Animales , Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos/farmacología , Desoxicitidina/farmacología , Susceptibilidad a Enfermedades , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Cinética , Masculino , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Trasplante Heterólogo , Células Tumorales Cultivadas , GemcitabinaRESUMEN
A human tumor xenograft model for cancer cachexia was established by growing a uterine cervical carcinoma, Yumoto, in nude mice. The tumor transplanted into the mice induced severe body weight loss (30% of body weight) when the tumor weight was only 1 g. In addition, other indicators for cachexia, such as adipose tissue and muscle wasting and hypoglycemia, were also observed in the tumor-bearing mice, suggesting that this is a proper model for experimental cachexia induced by a human tumor. We then examined the association of this model with various cytokines, such as tumor necrosis factor alpha, interleukin (IL)-1alpha, IL-1beta, IFN-gamma, IL-6, and leukemia inhibitory factor, and identified human IL-6, which was produced by the tumor cells, as a mediator of cachexia. A neutralizing antibody against hIL-6 administered to the mice after the development of cachexia symptoms significantly improved body weight loss, adipose tissue wasting, hypoglycemia, acute phase reaction, and leukocytosis, although it did not suppress the tumor growth. These results demonstrate that the hIL-6 produced by the tumor cells is an essential mediator of the cachexia induction in this model.