Comparative antitumor activity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in combination with radiation therapy in mice bearing colon 26 adenocarcinoma

The present study compared the antitumor activities of chemotherapy with 5-fluorouracil (5-FU) and with its prodrug 5'-deoxy-5-fluorouridine (5'-DFUR) in combination with radiotherapy on a solid colon 26 adenocarcinoma in the mouse. A single administration of 5'-DFUR immediately after local irradiation on day 10 after tumor inoculation produced more than additive antitumor effects, while only an additive effect was observed in the combined treatment with 5-FU and radiation. This over-additive effect of 5'-DFUR was more obvious in a fractionated-dose treatment schedule, where the same combined modality treatment was given three times on days 6, 10 and 14 after inoculation of the tumor cells. 5'-DFUR enhanced the radiation effects on the tumor in terms of the delay in tumor growth as well as the increase in the survival time. 5-FU produced only a marginal additive antitumor effect. Furthermore, radiation damage to normal tissues (skin damage by local irradiation and bone marrow and spleen damage by whole-body irradiation) was not enhanced by 5'-DFUR, though radiation damage to the thymus was additive. On the other hand, 5-FU produced toxic effects that were additive for all normal tissues tested. Thus, at doses that were the most effective against tumors, relative therapeutic gain factors (the ratio of the effect on tumors to that on the bone marrow) of 5'-DFUR and 5-FU were 1.24 and 0.49, respectively. These results suggest that 5'-DFUR will have a greater potential than 5-FU in combined modality treatment of cancer patients.     

Comparative Antitumor Activity and Intestinal Toxicity of 5'-Deoxy-5-fluorouridine and Its Prodrug Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine

N⁴-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09–1390), a prodrug of the cytostatic 5'-deoxy-5-fluorouridine (5'-DFUR), was synthesized with the aim of reducing of the dose-limiting toxicity of 5'-DFUR, which is diarrhea. In mice bearing Lewis lung carcinoma, 5'-DFUR given po produced a substantial amount of 5-fluorouracil (5-FU) in the intestinal tract as well as in tumors, where the enzyme pyrimidine nucleoside phosphorylase, essential for conversion of 5'-DFUR to 5-FU, is predominantly located. With the oral administration of Ro 09–1390 only a small amount of 5-FU was formed in the intestine; however, the administration of Ro 09–1390 and 5'-DFUR at the same dose produced similar amounts of 5-FU in tumor tissues. These differences in metabolism were reflected in their toxicity and antitumor efficacy. The administration of 5'-DFUR resulted in damage to the intestinal mucosal membrane and diarrhea in normal mice, whereas Ro 09–1390 was much less toxic to the intestinal tract. As regards antitumor activity, Ro 09–1390 and 5'-DFUR at equivalent doses inhibited the growth of Lewis lung carcinoma to similar extents. Since Ro 09–1390 was much less toxic to the intestinal tract than 5'-DFUR, mice bearing Lewis lung carcinoma could be given Ro 09–1390 daily over a longer period and at a higher dose, resulting in a longer survival time.     

Comparative antitumor activity and intestinal toxicity of 5'-deoxy-5-fluorouridine and its prodrug trimethoxybenzoyl-5'-deoxy-5-fluorocytidine

N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390), a prodrug of the cytostatic 5'-deoxy-5-fluorouridine (5'-DFUR), was synthesized with the aim of reducing of the dose-limiting toxicity of 5'-DFUR, which is diarrhea. In mice bearing Lewis lung carcinoma, 5'-DFUR given po produced a substantial amount of 5-fluorouracil (5-FU) in the intestinal tract as well as tumors, where the enzyme pyrimidine nucleoside phosphorylase, essential for conversion of 5'-DFUR to 5-FU, is predominantly located. With the oral administration of Ro 09-1390 only a small amount of 5-FU was formed in the intestine; however, the administration of Ro 09-1390 and 5'-DFUR at the same dose produced similar amounts of 5-FU in tumor tissues. These differences in metabolism were reflected in their toxicity and antitumor efficacy. The administration of 5'-DFUR resulted in damage to the intestinal mucosal membrane and diarrhea in normal mice, whereas Ro 09-1390 was much less toxic to the intestinal tract. As regards antitumor activity, Ro 09-1390 and 5'-DFUR at equivalent doses inhibited the growth of Lewis lung carcinoma to similar extents. Since Ro 09-1390 was much less toxic to the intestinal tract than 5'-DFUR, mice bearing Lewis lung carcinoma could be given Ro 09-1390 daily over a longer period and at a higher dose, resulting in a longer survival time.     

5'-DFUR (doxifluridine)

5'-DFUR is converted to 5-FU by pyrimidine nucleoside phosphorylase. The activity of this enzyme is higher in tissue tissue than in most normal tissues, leading to a significantly higher conversion to 5-FU and 5-FU concentration in the tumor tissue than in normal tissue and serum. This activation mechanism provides this compound with high tumor selective toxicity. Based on these characteristics, 5'-DFUR has shown significant antitumor activity with less toxicity and immunosuppressive activity in experimental models. In the clinical study, 5'-DFUR has shown antitumor activity in gastric, colo-rectum and breast cancer. Especially in breast cancer, high response was observed including CR cases and also suggested a fast onset of action and long duration of efficacy. In the safety, major adverse reaction was diarrhea but it was controllable. Bone marrow suppression and CNS toxicity were very mild. 5'-DFUR can be a good candidate for the combination regimen and surgical adjuvant chemotherapy.     

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect

Antiangiogenic therapy could destroy tumor vasculature and inhibit tumor growth. It might inhibit tumor growth significantly when used as a single treatment modality and its therapeutic benefit may even be greater when used in combination with established treatment modalities such as radiation therapy (RT). In the present report, we investigated the effect of recombinant human plasminogen kringle 5 domain (rhK5) in combination with ionizing radiation on angiogenesis, tumor growth and survival in a murine Lewis lung carcinoma (LLC) tumor model. Combined treatment using rhK5 and radiotherapy displayed obvious suppressive effect on LLC tumor growth as compared with single treatment with either modality (p < 0.05), and resulted in a more additive effect on tumor growth delay in this model. In addition, combined treatment significantly enhanced the survival of mice and no toxic effect, such as weight loss, was observed. The significant antitumor effect of rhK5 plus radiation was associated with a direct suppression effect on early neoangiogenesis and tumor cell apoptosis. Furthermore, the expression of VEGF and HIF-1alpha in tumor tissue correlated well with decreased vessel density. The results suggest that rhK5 significantly enhances the antitumor activity of RT and could be a potent adjuvant therapeutic approach to improve the efficacy of radiotherapy for lung cancer.     

Antitumor activity of 5'-deoxy-5-fluorouridine in human digestive organ cancer xenografts and pyrimidine nucleoside phosphorylase activity in normal and neoplastic tissues from human digestive organs.

5'-Deoxy-5-fluorouridine (5'-DFUR) is believed to be metabolized to 5-fluorouracil (5-FU) by pyrimidine nucleoside phosphorylase (PyNPase). PyNPase activity is reported to be higher in neoplastic tissues than in normal tissues, and this has been proposed as an explanation for the selective cytotoxicity of 5'-DFUR against tumors. In the present study, PyNPase activity was measured in 95 neoplastic and normal specimens from human digestive organ tissues. In specimens from the esophagus, stomach, intestine and pancreas, PyNPase activity was higher in neoplastic tissues than in normal tissues. However, PyNPase activity in non-malignant liver tissues, especially cirrhotic liver tissues, was much higher than in the normal tissues of the other digestive organs. PyNPase activity in non-malignant liver tissues was a high as in primary liver tumors, and PyNPase activity in metastatic liver tumors was lower than in primary tumors and non-malignant cirrhotic tissues. The in vivo antitumor activities of oral 5'-DFUR and intravenous 5-FU were also assessed in 6 human digestive organ cancer xenograft lines transplanted subcutaneously in nude mice, and the relationship between the in vivo antitumor effects of 5'-DFUR and PyNPase activity in the tumors was assessed. However, there was no statistically significant correlation between them. Although the in vivo antitumor effect of intravenous 5-FU correlated significantly with the in vitro sensitivity of the tumors to 5-FU (assessed by DNA synthesis inhibition assay), the in vivo effects of 5'-DFUR did not correlate with the in vitro sensitivity to 5-FU. It is suggested that: (a) the liver may be the major site for metabolizing 5'-DFUR to 5-FU, and (b) measuring PyNPase activity in the tumor may not be a useful indicator for chemotherapy with 5'-DFUR.     

Anticancer treatment with a combination of antimetabolites of polyamine and pyrimidine

A combined efficacy of the polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG) with two fluorinated pyrimidines was studied. DFMO, MGBG, 5-FU and 5'-deoxy-5-fluorouridine (5'-DFUR) were administered intraperitoneally to BALB/c nu/nu mice bearing xenotransplanted human gastric cancer for 5 consecutive days. Similar antitumor efficacies were observed in 3 groups treated with DFMO plus MGBG, DFMO, MGBG plus 5-FU as well as DFMO, MGBG plus 5'-DFUR. The two groups on 5-FU or 5'-DFUR alone did not differ in antitumor effects from the control, although reasonable levels of 5-FU were involved in tumor tissues. Hepatic and splenic 5-FU levels after 5-FU administration were significantly higher than those after 5'-DFUR, and marked decrease in mouse body weight was caused by 5-FU alone as well as 5-FU plus polyamine antimetabolites for 5 consecutive days. DNA biosynthesis and spermine levels in the tumor tissues on day 2 after cessation of the treatments dropped in 3 groups with DFMO plus MGBG, DFMO, MGBG plus 5'-DFUR as well as DFMO, MGBG plus 5-FU, while on day 6 there was little difference between the control and treated groups. These data suggest that combination with 5-FU or 5'-DFUR does not enhance the antitumor activity of polyamine antimetabolites by this experimental regimen.     

Optimal dosing schedule in combination therapy with irinotecan and doxifluridine in a human colorectal cancer xenograft model

A combination therapy with CPT-11 and 5-FU/LV has been recently established as a first-line therapy for metastatic colorectal cancer. However, severe adverse effects have also been reported from this combination therapy, and a modality to reduce the adverse effects is desired. 5'-DFUR, a pro-drug of 5-FU, shows less myelotoxicity than 5-FU, and thus it may be a better partner to combine with CPT-11. However, since each drug has the possibility of inducing diarrhea, there is concern about their use in combination therapy. Therefore, in the present study, our aim was to establish an optimal schedule in murine models, which shows no increase in diarrhea but maintains potent antitumor activity. In non-tumor bearing mice, CPT-11 was given i.v. at 100 mg/kg/day q2d x 3, and 5'-DFUR was given p.o. at 172 mg/kg/day daily for 14 days. Each of these doses caused diarrhea in the single treatment. CPT-11 was administered simultaneously or sequentially with 5'-DFUR. With the simultaneously administered schedule, the diarrhea appeared stronger than that found in the CPT-11 single or in the 5'-DFUR single treatment groups. On the other hand, with the sequentially administered schedule the diarrhea was not much stronger than that found in the single agent treatment groups. When CPT-11 and 5'-DFUR administrations were separated by three-day intervals, the diarrhea was not augmented at all. In mice bearing human colorectal cancer COLO 205, the antitumor activity of CPT-11 in the combination with 5'-DFUR was additive in all of the examined schedules. The efficacy in the sequential schedule was the same as in the simultaneous schedule. These results suggest that a sequential administration schedule of CPT-11 and 5'-DFUR would be more tolerable than and equally efficacious to the simultaneous administration schedule. Clinical study of this sequential administration in combination therapy is warranted.     

Phase I and pharmacologic study of 72-hour infused 5-fluorouracil and hyperfractionated cyclical radiation

We have studied 21 patients infused for 72 hours with 5-Fluorouracil (5-FU) at progressive doses combined with hyperfractionated radiation. The schedule was chosen as being one capable of inducing 5-FU radiosensitization (RS). All patients were started at a daily 5-FU dose of 40 mg/kg/24 hours; doses were then escalated with each subsequent treatment cycle to limiting toxicity or until taken off study. Patients received between one and six infusion cycles. Every treatment cycle included coincident hyperfractionated radiation to various body areas including the abdomen, chest, and head and neck region. Radiation fractionation was invariant; 1,000 rad were delivered in four equal fractions. Two fractions of 250 rad each were given on days 1 and 2 of each three day 5-FU cycle, i.e. at approximately 0, 8, 24, and 32 hours into the drug infusion. Patients were followed for toxicity; serum 5-FU concentrations were determined using a high pressure liquid chromatographic assay. 5-FU clearances were calculated from the mean serum drug levels and the infused drug dose. The toxicity spectrum was not found to be significantly different from infused drug alone in this dose range save when the head and neck region received coincident irradiation. In that region the two anticipated toxicities combined in what appears to be a synergistic fashion to enhance mucositis. Most toxicities including gastrointestinal and bone marrow appeared dependent on the mean serum 5-FU level as did mucositis itself. 5-FU clearance was found to be non-linear in this dose region but did not appear influenced by radiation to any part of the body. This study shows that 72-hour infused 5-FU can be combined with external beam radiation and will produce reasonably predictable toxicity patterns which depend on the region of the body being irradiated. 5-FU toxicity correlates with mean serum drug level which is itself dependent on 5-FU clearance. Minor variations in 5-FU clearance therefore probably contribute to the natural range found in the dose-response relationship for infused 5-FU toxicities. Future studies should integrate this understanding of 5-FU pharmacokinetics into treatment regimens. The combination of infused 5-FU and coincident radiation appears useful in treating several tumor types, particularly squamous and squamous-like cancers. However, further scheduling and radiation fractionation studies are desirable to optimize 5-FU RS in man and to quantify late effects.     

Tumor treatment by sustained intratumoral release of 5-fluorouracil: effects of drug alone and in combined treatments

: To evaluate an intratumoral polymer implant for sustained delivery of 5-fluorouracil (5-FU) in a mouse tumor model.

: 5-FU was incorporated into a polyanhydride-based polymer, bis(p-carboxyphenoxy)propane sebacic acid (CPP:SA) and implanted in RIF-1 mouse fibrosarcoma growing s.c. The effectiveness of treatment was evaluated by tumor growth delay. External beam radiation was ⁶⁰Co gamma rays, and the source of interstitial radiation was implanted ¹²⁵I seeds. A second drug, cis-diamminedichloroplatinum (cis-DDP), was administered by intraperitoneal injection or by osmotic pump.

: For drug/polymer implant alone, the tumor growth delay was proportional to the amount of drug in the implant. The 5-FU polymer implant was most effective when combined with cis-DDP or with acute or fractionated radiation, and in some cases, the effects of combined treatments were greater than additive. The most effective combination was intratumoral 5-FU and low-dose-rate radiation delivered from an interstitial radiation source.

: Results indicate that 5-FU can be effectively delivered by polymer implant and that this mode of delivery is particularly appropriate for combined treatments.     

MCF-7 growth inhibition by ultraviolet radiation and 5-fluorouracil: the importance of treatment sequence

Effective treatment of certain cancers with 5-fluorouracil (5-FU) and irradiation is well established; however, the most effective combination of these agents remains controversial. Although 5-FU has been identified as a radiosensitizer, the mechanism of action remains unknown. To assess the effect of combination, 5-FU and ultraviolet (UV), we constructed a new in vitro model with MCF-7 human breast cancer cells that measures growth inhibition and morphologic changes in nuclear argyrophilic nucleolar organizer regions (AgNORs). Cells were incubated in media containing 0, 50, 100 and 500 ng/ml 5-FU for 48 h, they were also exposed to UV irradiation of 90 J/m(2) at the beginning, middle, or end of the incubation period. The cells were incubated for an additional 48 h with 5-FU free media. A combined treatment with 5-FU and UV radiation demonstrated an additive inhibitory effect. The strongest growth inhibition was observed when UV exposure was at the beginning of the 5-FU treatment at 5-FU concentrations of 100 and 500 ng/ml. To elucidate the activity of 5-FU radiosensitization, we investigated the aggregation Pof AgNOR, which we previously established to reflect rRNA inhibition. A combined treatment with 5-FU and UV radiation accelerated the rate of AgNOR aggregation at 5-FU concentrations of 50 and 100 ng/ml. The timing of UV irradiation did not affect the rate of AgNOR aggregation. A combined treatment with 5-FU and UV radiation showed an additive inhibitory effect on MCF-7 cell growth that might be explained, in part, by rRNA inhibition.     

Combined effects of interferon alpha-A/D with fluoropyrimidine derivatives in the subrenal capsule assay

The combined effects of interferon alpha-A/D (IFN alpha-A/D) with 5-fluorouracil and fluoropyrimidine derivatives such as 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur), UFT, 1-hexylcarbamoyl-5-fluorouracil (HCFU) and 5'-deoxy-5-fluorouracil (5'-DFUR), were examined by 4-day subrenal capsule assay. Four human tumor xenografts serially transplanted in athymic mice, H-111, SH-10 established from gastric cancers, CH-4 and CH-5 from colon cancers, were used. In this experiment, the adequate dose of each agent was estimated as 50 mg/kg for 5-FU, 473 mg/kg for tegafur, 433 mg/kg for UFT, 50 mg/kg for HCFU, 185 mg/kg for 5'-DFUR and 1 x 10(5) IU for IFN alpha-A/D, respectively. When synergistic, additive and subadditive effects were defined as positive combined effects, all combinations produced positive combined effects against H-111 and CH-5, while negative ones were observed for all combinations against CH-4. The combinations of 5-FU, HCFU and 5'-DFUR with IFN alpha-A/D produced synergistic effects against SH-10. These results indicate that the combination therapy of 5-FU and fluoropyrimidine derivatives with IFN alpha-A/D would be useful.     

Liposomal prednisolone phosphate potentiates the antitumor activity of liposomal 5-fluorouracil in C26 murine colon carcinoma in vivo

The antitumor efficacy of 5-fluorouracil (5-FU) in advanced colorectal cancer (CRC) is hindered not only by the low therapeutic index, but also by tumor cell resistance to this cytotoxic drug. Therefore, to enhance the 5-FU antitumor activity, the present research used a novel tumor-targeted therapy based on the co-administration of 5-FU encapsulated in long-circulating liposomes (LCL-5-FU) together with liposomal prednisolone phosphate (LCL-PLP), a formulation with known anti-angiogenic actions on C26 murine colon carcinoma cells. Thus, we assessed the in vivo effects of the combined liposomal drug therapy on C26 carcinoma growth as well as on the production of molecular markers with key roles in tumor development such as angiogenic, inflammatory, and oxidative stress molecules. To get further insight into the polarization state of tumor microenvironment after the treatment, we determined the IL-10/IL-12p70 ratio in tumors. Our results showed that combined liposomal drug therapy inhibited almost totally tumor growth and was superior as antitumor activity to both single liposomal drug therapies tested. The antitumor efficacy of the combined therapy was mainly related to the anti-angiogenic and anti-inflammatory actions on C26 carcinoma milieu, being favored by its controlling effect on intratumor oxidative stress and the skewing of polarization of tumor microenvironmental cells toward their antineoplastic phenotypes. Thus, our study unveils a promising treatment strategy for CRC that should be furthermore considered.     

Increased cytotoxicity and bystander effect of 5-fluorouracil and 5-deoxy-5-fluorouridine in human colorectal cancer cells transfected with thymidine phosphorylase.

5-Fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR), a prodrug of 5-FU, are anticancer agents activated by thymidine phosphorylase (TP). Transfecting the human TP cDNA into cancer cells in order to sensitize them to these pyrimidine antimetabolites may be an important approach in human cancer gene therapy research. In this study, an expression vector containing the human TP cDNA (pcTP5) was transfected into LS174T human colon carcinoma cells. Eight stable transfectants were randomly selected and analysed. The cytotoxic effects of 5-FU and 5'-DFUR were higher in TP-transfected cells as compared to wild-type cells. The maximal decreases in the IC50 were 80-fold for 5-FU and 40-fold for 5'-DFUR. The increase in sensitivity to these pyrimidines of TP-transfected cells significantly correlated with the increase in both TP activity and TP expression. Transfected clone LS174T-c2 but not wild-type cells exhibited formation of [3H]FdUMP from [3H]5-FU. In addition the LS174T-c2 clone enhanced the cytotoxic effect of 5'-DFUR, but also that of 5-FU, towards co-cultured parental cells. For both anti-cancer agents, this bystander effect did not require cell-cell contact. These results show that both 5-FU or 5'-DFUR could be used together with a TP-suicide vector in cancer gene therapy.     

Pharmacokinetic Modulation of Plasma 5-Fluorouracil Concentrations to Potentiate the Antitumor Activity of Continuous Venous Infusion of 5-Fluorouracil

Methods for pharmacokinetic modulation of the plasma 5-fluorouracil (5-FU) level to increase antitumor activity during continuous venous infusion (CVI) of low doses of 5-FU were examined in Yoshida sarcoma-bearing rats. These methods were additional infusion of 5-FU for a short period (4 h) or oral administration of LIFT or Tegafur during long-term CVI of 5-FU that alone gave a plasma 5-FU level of about 50 ng/ml. The antitumor effect on Yoshida sarcoma was markedly potentiated when an additive dose of 5-FU combined with 3-cyano-2,6-dihydroxypyridine (CNDP), a potent inhibitor of 5-FU degradation, giving a plasma level of about 500 ng/ml, was infused for 4 h. A similar increase in the antitumor effect was observed with oral administration of a conventional dose of UFT during CVI of 5-FU without CNDP, giving a plasma level of 30 to 60 ng/ml. These results suggest that the antitumor effect of CVI of 5-FU can be potentiated by pharmacokinetic modulation of the 5-FU concentration in the blood.     

Conversion of 5'-deoxy-5-fluorouridine to 5-FU by pyrimidine nucleoside phosphorylases in normal and tumor tissues from rodents bearing tumors and cancer patients

Enzyme levels of pyrimidine nucleoside phosphorylase, which is an essential enzyme for the phosphorolysis of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU), in normal and tumor tissues were investigated. In all mouse strains tested, the enzyme level was found to be higher in the small intestine and stomach than other tissues, while in rats a higher level of the enzyme in the lung was also observed additionally. The enzyme levels of tumor tissues varied in tumor cell lines transplanted. P388 leukemia, Ehrlich ascites carcinoma, sarcoma 180, colon 26 carcinoma, and Lewis lung carcinoma cells contained high levels of the enzyme and the mice bearing these tumors responded well to the therapy with 5'-DFUR than its active metabolite 5-FU, while 5'-DFUR did not show clear advantage over 5-FU against L1210 or LSTRA leukemia, in which the enzyme levels were low. These results indicate that there is some correlation between the enzyme level and antitumor efficacy of 5'-DFUR. In human specimens, the enzyme levels were 2-6 times higher in tumors than those of the corresponding normal tissues and those adjacent to the tumors. These results predict that 5'-DFUR seemed to be converted efficiently to 5-FU also in human tumors.     

Protection of Survival and Hematopoiesis in Irradiated Mice by 5-FIuorouracil

The effects of whole-body irradiation on survival and the hematopoietic system were studied in mice treated with 5-fluorouracil (5-FU). Animals (ddY-SLC male mice, 8–10 weeks old) were injected with 5-FU (i.p.) as a single dose (150 mg/kg) at various times before or after irradiation with X-rays at graded doses (4.8 to 7.6 Gy). The treatment of mice with 5-FU 5 days before irradiation was the most effective for the reduction of radiation lethality, having a radioprotective effect. The dose reduction factor (DRF) was 1.24. However, treatment with 5-FU at 1 day and 2 hours before, or at various times after irradiation significantly increased the radiation lethality compared to the untreated controls, creating a radiosensitizing effect. The decrease or the increase of radiation lethality exhibited by 5-FU was similar to. the radiation-dose relationship pattern shown by endogenous and exogenous CFU-S. The pattern of change of thrombocyte counts in the circulating blood after irradiation was greatly modified by pretreatment with 5-FU 5 days before irradiation, effectively lessening the radiation-induced depression. In contrast, the post-irradiation patterns of leukocyte and erythrocyte variation did not show any significant change due to pretreatment with 5-FU.     

Preferential inhibition of bone metastases by 5'-deoxy-5-fluorouridine and capecitabine in the 4T1/luc mouse breast cancer model

5'-deoxy-5-fluorouridine (5'-DFUR) and capecitabine are oral anti-cancer agents, which are enzymatically converted to 5-fluorouracil (5-FU) by thymidine phosphorylase in humans and uridine phosphorylase in mice. Since the activity of these phosphorylases is higher in cancerous tissue than in normal tissue, systemic administration of 5'-DFUR and capecitabine achieves high intratumoral 5-FU levels and low adverse effects on non-tumoral tissue. Accordingly, 5'-DFUR and capecitabine are widely used for the treatment of cancer patients. In the present study, we examined the effects of 5'-DFUR and capecitabine on bone metastases, one of the most common complications of breast cancer, using an animal model in which inoculation of 4T1/luc mouse breast cancer cells into the mammary fat pads of female BALB/c mice developed spontaneous metastases in distant organs including bone, lung and liver. Mice received 4T1/luc cell inoculation in the mammary fat pad at day 0 and oral 5'-DFUR (31, 62, 123 or 246 mg/kg) or capecitabine (90, 180 or 359 mg/kg) daily from day 7 to day 21. Both 5'-DFUR and capecitabine significantly inhibited orthotopic tumor formation and distant metastases to bone, lung and liver in a dose-dependent manner. Of note, the lowest dose of 5'-DFUR (31 mg/kg) and capecitabine (90 mg/kg), which failed to inhibit orthotopic tumor development and the lung and liver metastases, significantly reduced the bone metastases. In conclusion, our results suggest that oral 5'-DFUR and capecitabine are effective for the treatment of primary and secondary breast tumors. Most notably, they also suggest that these agents are preferentially beneficial for bone metastases.     

Antitumor activity of a new fluoropyrimidine derivative, 5'-deoxy-5-fluorouridine, against murine and human experimental tumors

5'-Deoxy-5-fluorouridine (5'-DFUR) was evaluated for antitumor activity against four murine tumors (L1210 leukemia, P388 leukemia, Lewis lung carcinoma, and B16 melanoma) and a human mammary carcinoma (MX-1) xenografted in athymic mice. Intraperitoneal administration of 5'-DFUR was ineffective against B16 melanoma implanted intraperitoneally and showed less marked antitumor activity against P388 and L1210 leukemias implanted intraperitoneally or intravenously as compared with that of 5-fluorouracil (5-FU) or 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), while oral administration of 5'-DFUR showed a similar or superior antitumor activity to that of 5-FU or FT-207 against L1210 leukemia implanted subcutaneously. 5'-DFUR showed a marked antitumor activity against MX-1 implanted subcutaneously and also showed slight antitumor activity against Lewis lung carcinoma implanted subcutaneously, while 5-FU and FT-207 did not show any significant antitumor activity against these tumors. These results suggest that 5'-DFUR may be worthy of clinical trial against solid tumors, especially cancers of the breast.