Biomedical subjects

M Iigo

Publications and source records attributed to M Iigo.

At least 73 records · Page 4Linked to original sources

PubMed1990

Differential effects of 2,2'-anhydro-5-ethyluridine, a uridine phosphorylase inhibitor, on the antitumor activity of 5-fluorouridine and 5-fluoro-2'-deoxyuridine.

2,2'-Anhydro-5-ethyluridine (ANEUR), a potent inhibitor of uridine phosphorylase, markedly potentiated the antitumor activity of fluorouridine (FUR) against murine mammary adenocarcinoma 755 in BDF1 mice and human colon adenocarcinoma LS174T in athymic-nude mice. Whereas ANEUR annihilated the antitumor activity of 5-fluoro-2'-deoxyuridine (FUdR) and 5'-deoxy-5-fluorouridine (DFUR) in the murine adenocarcinoma 755 system, it did not alter the antitumor activity of FUdR in the human adenocarcinoma LS174T system. In vitro, ANEUR proved inhibitory to the phosphorolytic cleavage of both FUR and FUdR by uridine phosphorylase, and this could explain why in vivo conversion of FUR and FUdR to 5-fluorouracil was suppressed. FUR can be held directly responsible for the antitumor effects observed in the murine adenocarcinoma 755 system, whereas in the activity against human adenocarcinoma LS174T may be mediated by both FUR and FUdR.

Adenocarcinoma↗

PubMed1990

Clinical significance of monitoring serum levels of 5-fluorouracil by continuous infusion in patients with advanced colonic cancer.

Serum concentrations of 5-fluorouracil (5-FU) given by continuous infusion to 19 patients with advanced colonic cancer were measured by an HPLC method, and steady-state concentration (SSc), area under the curve (AUC72) and total body clearance (Cl) were calculated as pharmacokinetic parameters. The serum level of 5-FU rapidly increased, reaching a plateau within 2 h after the start of administration. There were positive correlations between the dose and both SSc (r = 0.578, P less than 0.01) and AUC72 (r = 0.558, P less than 0.05). When the patients were divided into toxic and non-toxic groups according to the degree of toxicity, the values for SSc and AUC72 in the toxic group were significantly higher than those in non-toxic patients. The Cl value in the toxic group was also significantly different from that in the non-toxic group when data were calculated on a log scale. Furthermore, no differences in these parameters between effective and non-effective in these parameters between effective and non-effective groups were detected when the patients were divided into two groups according to anti-neoplastic responses. These results indicate that increased serum concentration does not always provide therapeutic benefits to patients receiving continuous infusions of 5-FU.

Adult↗

PubMed1990

Effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine on life-span and 5-fluorouracil metabolism in mice with hepatic metastases.

5-Fluorouracil (5FU) is rapidly metabolised in the liver by dihydrouracil dehydrogenase. Bromovinyluracil is formed in the liver from (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) by pyrimidine nucleoside phosphorylase and is a potent inhibitor of dihydrouracil dehydrogenase. The co-administration of 5FU (intravenously) and BVDU (orally) was investigated in normal BDF1 mice and in those bearing liver metastases of Lewis lung carcinoma. 5FU alone rapidly disappeared from plasma and liver within 60 min of dosing. Administered with BVDU, 5FU persisted in plasma and liver for 60-180 min. The combination also significantly enhanced the life-span of tumour-bearing mice. 5FU plus BVDU may have therapeutic potential in the treatment of primary and secondary liver tumours.

Animals↗

PubMed1990

Therapeutic activity and tissue distribution of ME2303, a new anthracycline containing fluorine, and its metabolites in mice bearing hepatic metastases of Lewis lung carcinoma.

Doxorubicin (DXR) and ME2303, a new fluorine-containing (C'-2) anthracycline derivative, were studied for their tissue distributions--particularly in the plasma, liver and bone marrow--following administration at the maximum tolerated doses to normal mice and mice bearing hepatic metastases of Lewis lung carcinoma. ME2303 was rapidly metabolized and disappeared rapidly from the plasma, liver and bone marrow. Its metabolites--the product of esterolysis (M1) and its reduced derivative at the C-14 position (M2)--remained for a long period except in bone marrow. On the other hand DXR remained in the analyzed tissues for a long period; an especially large amount of DXR was found in the bone marrow even at 24 h after administration of the drug while, in the case of ME2303, by this time even its metabolites had disappeared. The concentrations of M1 and DXR in the liver at 2 h were about 50- and 300-fold higher than their plasma concentrations. The tissue distributions in the normal mice and hepatic-metastases-bearing mice showed no significant differences. Regarding the antitumor effects of ME2303, M1, M2 and DXR in the hepatic-metastases-bearing mice, ME2303 was the most effective compound, and M1 was also active; DXR showed only a marginal effect, and M2 showed no effect.

Animals↗

PubMed1990

Optimal treatment regimens for 5'-deoxy-5-fluorouridine, with or without (E)-5-(2-bromovinyl)-2'-deoxyuridine, against various tumors in mice.

The antitumor activity of 5'-deoxy-5-fluorouridine (DFUR), a prodrug of 5-fluorouracil (5-FU), is markedly enhanced if DFUR treatment is combined with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). Combined oral administration of DFUR (10 mg/kg) and BVDU (10 mg/kg) three times (every 3 h) per day for 5 days afforded greater antitumor activity than a single dose of DFUR (300 mg/kg/day) for 5 days in mice bearing either adenocarcinoma 755 or Lewis lung carcinoma, while in the colon 26 system the antitumor effects of both treatment regimens were equivalent. Thus, a low-dose regimen of DFUR when combined with BVDU provides a similar or greater antitumor activity than a high-dose regimen of DFUR that is not combined with BVDU. The area under the curve of plasma 5-FU following a treatment with the combination of DFUR (10 mg/kg) and BVDU (10 mg/kg) was equal to that following DFUR (300 mg/kg) treatment.

Adenocarcinoma↗

PubMed1990

Lack of correlation between interferon levels induced by polyribonucleotides and their antimetastatic effect.

The inhibitory effect of poly(A)poly(U) on the pulmonary metastasis of B16-F10 melanoma was examined in comparison with that of poly(I,C)-L,C and poly(I)poly(C). The correlation between interferon (IFN) level and antimetastatic effect was also investigated. Intraperitoneal injection of poly(A)poly(U) (50 mg/kg) into C57BL/6 mice 24 h before intravenous inoculation of B16-F10 melanoma (1 X 10(5] caused a significant decrease (p less than 0.01) in the number of pulmonary nodules 14 days after tumor challenge. But poly(I,C)-L,C (1 or 0.2 mg/kg) and poly(I)poly(C) (5 mg/kg or 1 mg/kg) did not. From the kinetic study of IFN levels induced by polyribonucleotides, poly(I,C)-L,C showed the most potent IFN-inducing activity, followed by poly(I)poly(C) and poly(A)poly(U), in this order. Plasma IFN reached a peak at 6 h and still continued to be detected at 24 h after intraperitoneal injection of the polyribonucleotides. Against B16-F10 melanoma, the cytotoxicity of spleen cells stimulated by poly(A)poly(U) (50 mg/kg) was significantly (p less than 0.05) higher than that of spleen cells stimulated by poly(I)poly(C) (5 mg/kg) both at 12 and 24 h after intraperitoneal injection of those agents. The above results that there is no correlation between the IFN levels induced by polyribonucleotides and their antimetastatic effect. More extensive study of poly(A)poly(U) might give more fruitful results, which will give valuable information for future clinical trials of this lowly toxic promising agent.

Animals↗

PubMed1990

Effect of recombinant interleukin-1 alpha, recombinant interleukin-2, recombinant interferon-beta, and recombinant tumor necrosis factor on subcutaneously implanted adenocarcinoma 755 and Lewis lung carcinoma.

The antitumor activity of recombinant human interleukin-1 alpha (rHIL-1 alpha), recombinant human tumor necrosis factor, and recombinant murine interferon-beta (rIFN-beta) was augmented by concomitant administration of recombinant human interleukin-2 (rHIL-2) in the treatment of adenocarcinoma 755. Especially when a divided dose (two doses/day) of rHIL-1 alpha or rIFN-beta was combined with a divided dose of rHIL-2, the antitumor effect was markedly potentiated. However, only a marginal effect was seen by combination of rHIL-1 alpha and/or rIFN-beta and rHIL-2 against Lewis lung carcinoma, a tumor that is resistant to cytokines.

Adenocarcinoma↗

PubMed1989

Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5'-deoxy-5-fluorouridine against adenocarcinoma 755 in mice. Correlation with pharmacokinetics of plasma 5-fluorouracil levels.

5'-Deoxy-5-fluorouridine (DFUR), whether or not combined with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was pursued in BDF1 mice from both a pharmacokinetic viewpoint, following a single oral dose administration, and an anticancer viewpoint, following 5 daily oral doses in mice inoculated subcutaneously with adenocarcinoma 755 tumor cells. Half-life (t1/2) values for the elimination of DFUR and 5-fluorouracil (5-FU) from plasma following DFUR (100 mg/kg) administration were about 0.80 and 0.39 hr, respectively. Plasma 5-FU AUC (area under the curve) values following oral DFUR (100 mg/kg) was 0.224 micrograms.hr/ml. If DFUR (100 mg/kg) was combined with BVDU (10 mg/kg) the t1/2 and AUC values for 5-FU increased from 0.39 to 1.24 hr, and from 0.224 to 1.699 micrograms.hr/ml, respectively. Thus, BVDU significantly increased the plasma levels of 5-FU. It had no effect on the plasma levels of DFUR. At 100 mg/kg, DFUR did not show a significant antitumor activity. At 500 mg/kg it effected a 90% inhibition in tumor growth. When combined with BVDU (10 mg/kg), DFUR at 100, 200 and 300 mg/kg reduced tumor growth by 96, 100 and 100%, respectively. The antitumor activity achieved by DFUR, in the presence or absence of BVDU, correlated highly significantly with the AUC values for plasma 5-FU.

Adenocarcinoma↗

PubMed1989

Changes in lymphocyte subsets following multiple administration of recombinant interleukin-2 plus recombinant interferon-beta or -gamma in tumor-bearing mice.

Treatment with a combination of recombinant human interleukin-2 (rHIL-2) and recombinant mouse interferon-beta (rIFN-beta) or -gamma (rIFN-gamma) showed a significant antitumor effect against sc adenocarcinoma 755 in mice, although treatment with either one alone had almost no effect. The combination of rHIL-2 and rIFN-beta caused regression of the tumor but the combination of rHIL-2 and rIFN-gamma did not. Injection of tumor-bearing mice with the combinations of rHIL-2 and rIFN resulted in marked increases in the total number of peritoneal lymphocytes, and the frequency of Lyt-2+ cells was more markedly increased by the combination of rHIL-2 and rIFN-beta than by the combination of rHIL-2 and rIFN-gamma. In Winn assay, elimination of the Lyt-2+ population abolished the protective capacity of the peritoneal cells. The subsets of thymocytes were drastically changed when mice were bearing a tumor or were treated with cytokines. In particular, Lyt-2+/L3T4+ cells were decreased in tumor-bearing mice, but many Lyt-2+/L3T4+ cells were maintained in the thymus by treatment with a cytokine alone. When treated with rHIL-2 and rIFN-beta, the Lyt-2+/L3T4+ cells were markedly decreased, while Lyt-2+/L3T4- T-cells were increased, but these subsets were little changed by treatment with rHIL-2 plus rIFN-gamma. Thus, injections of rHIL-2 and rIFN-beta into tumor-bearing mice resulted in a high frequency of Lyt-2+/L3T4- cells in the peritoneal cavity, together with changes in the T-cell subsets in the thymus. These results suggest that maturation of T-cells in the thymus may be an important step in the pathway by which cytokine treatment brings about regression of tumors.

Adenocarcinoma↗

PubMed1989

Enhanced antitumor effect of 5'-deoxy-5-fluorouridine by oral administration with L-cysteine.

When given orally in combination with L-cysteine, 5'-deoxy-5-fluorouridine (DFUR) brought about a significant reduction in the growth of adenocarcinoma 755 and a significant prolongation of life-span in mice bearing Lewis lung carcinoma without increased toxicity to the host as compared with DFUR alone, though L-cysteine alone did not show an appreciable antitumor activity. Moreover, the combination of DFUR and L-cysteine resulted in a marked retardation of growth of human colon tumor LS174T transplanted into nude mice. Thus, the potency of DFUR was increased by L-cysteine. Pharmacokinetic studies revealed that after DFUR administration, plasma DFUR and 5-fluorouracil (5-FU) levels rapidly declined, but that, in the combination with L-cysteine, the plasma clearances of DFUR and 5-FU were slowed down considerably. In the tumor, DFUR and 5-FU levels were similar to those in the plasma. Such a prolongation of DFUR and 5-FU levels in plasma and tumor may produce the enhancement of antitumor effect seen with the combination of DFUR and L-cysteine.

Adenocarcinoma↗

PubMed1989

Enhanced antitumor effect of combination therapy with interleukin-2 and polyribonucleotides against adenocarcinoma 755.

Human recombinant interleukin-2 (IL-2) and interferon (IFN) inducers in combination were evaluated for their in vivo antitumor efficacy in relation to s.c.-implanted adenocarcinoma 755 in C57BL/6 mice. Two IFN inducers, polyinosinic-polycytidylic acid [poly(I)poly(C)] and polyadenylic-polyuridylic acid [poly(A)poly(U)], induced high IFN production in various tissues for a long time compared to treatment with murine interferon-beta. Especially, poly(I)poly(C) at 5 mg/kg, the maximum tolerated dose, produced the highest level of IFN in the tumor, but the tumor did not show regression. Poly(I)poly(C), however, brought about marked regression of the tumor when administered together with IL-2. This combination resulted in cure of some mice when both drugs were administered intraperitoneally. Intraperitoneal injection of IL-2 in combination with poly(I)poly(C) was more effective than intravenous injection of IL-2. The combination of IL-2 and poly(A)poly(U) also showed an enhanced antitumor effect. Thus, endogenous IFN produced by IFN inducers as well as exogenous IFN as reported previously potentiated the antitumor effect when administered together with IL-2. The degree of potentiation by combination of IL-2 and IFN inducers may depend on the level of IL-2 and IFN at the injection site.

Adenocarcinoma↗

PubMed1988

Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenocarcinoma 755 in mice. Increased therapeutic index and correlation with increased plasma 5-fluorouracil levels.

A marked inhibition of the growth of solid tumor adenocarcinoma 755 was achieved by the combination of 5-fluorouracil (5-FU) with bromovinyldeoxyuridine (BVDU). The therapeutic index (LD50/ED50) for the combination of BVDU plus 5-FU was 8.1 and 3.9 upon intraperitoneal (i.p.) or oral (p.o.) administration, respectively. The therapeutic index of i.p. 5-FU given alone was 2.3, whereas for p.o. 5-FU given alone no therapeutic index could be established because of insufficient activity of the compound. Thus, the therapeutic index of 5-FU increased significantly when combined with BVDU. Pharmacokinetic studies revealed that upon i.p. or p.o. 5-FU administration plasma 5-FU levels rapidly declined, but that, in the combination with BVDU, the plasma clearance of 5-FU, especially following p.o. administration, was slowed down considerably. Antitumor activity of 5-FU correlated with AUC (area under the concentration x time curve), within the plasma 5-FU concentration range from 0.02 to 0.4 microgram/ml.

Adenocarcinoma↗

PubMed1988

In vivo antitumor activity of multiple injections of recombinant interleukin 2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors.

We have used several transplantable experimental murine tumors to evaluate the potentiation of antitumor activity by a combination of human recombinant interleukin 2 (rHIL2) and recombinant interferons (rIFNs). The combination of rHIL2 and either human hybrid recombinant alpha-interferon A/D (rIFN-alpha A/D) or mouse recombinant beta-interferon (rIFN-beta) induced the s.c. adenocarcinoma 755, which had been established for 8 days, to regress, although rHIL2 or the rIFNs alone hardly inhibited the tumor's growth. Eight injections of the rHIL2-rIFN-alpha A/D combination cured 38% of the tumor-bearing mice. The rHIL2-rIFN-beta combination achieved a complete cure only when given in more than 13 injections. The administration of rHIL2 and mouse recombinant gamma-interferon (rIFN-gamma) markedly inhibited tumor growth of the s.c. established adenocarcinoma 755, but did not cure any of the mice. Other tumors, B16-F10 melanoma, and colon tumors 38 and 26 responded almost as well to a rHIL2-rIFN-alpha A/D or -beta combination, but not to a rHIL2-rIFN-gamma combination. The growth of Lewis lung carcinoma was inhibited to a lesser extent by all combinations, for which there were no long-term survivors. The combination therapy of rHIL2 and rIFN-beta produced a marked regression of the tumor in beige mice which have low natural killer activity, suggesting the activated natural killer cells not to be responsible for the therapeutic effect. And T-cell immunity may be important in the regression of s.c. established tumors, because of the lesser potentiation of antitumor activity in athymic mice. These results demonstrate that combination therapies of rHIL2 and rIFN-alpha A/D or -beta can function synergistically in the various s.c. established murine tumor systems and give further evidence in support of their clinical potential.

Animals↗

PubMed1988

Comparative study of the antitumor effect of two types of murine recombinant interferons, (beta) and (gamma), against B16-F10 melanoma.

A comparative study of the antitumor effect of murine recombinant interferon(beta) less than Mu-rIFN(beta) greater than and murine recombinant interferon(gamma) less than Mu-rIFN(gamma) greater on B16-F10 melanoma was conducted. Administration of Mu-rIFN(gamma) i.p. into C57BL/6 mice on days 1 to 7 produced a higher suppressive effect than Mu-rIFN(beta) both on the growth of s.c. implanted tumor and on the formation of artificial pulmonary metastasis. Pharmacokinetic study of Mu-rIFN(gamma) demonstrated that high plasma levels were retained for a long time. In clonogenic assay, Mu-rIFN(gamma) at 1000 units/ml showed about 80% inhibition of colonies of B16-F10 melanoma. However, Mu-rIFN(beta) hardly inhibited the colonies, even at 1000 units/ml. Augmentation of natural killer (NK) cytotoxicity was much greater with Mu-rIFN(beta) than Mu-rIFN(gamma), whereas Mu-rIFN(gamma) enhanced the cytotoxicity of peritoneal macrophages more strongly than Mu-rIFN(beta). Injection of Mu-rIFN(gamma) i.p. 1 day before tumor challenge also inhibited the formation of pulmonary metastasis of B16-F10 melanoma. However, pretreatment of mice with carrageenan significantly suppressed the inhibitory effect of Mu-rIFN(gamma). From these results, it is suggested that the inhibitory effect of Mu-rIFN(gamma) on the tumor growth and metastases of B16-F10 melanoma is mediated partly by direct antitumor effect and partly by the activation of macrophages, and that the augmentation of NK activity contributes mainly to the antitumor effect of Mu-rIFN(beta).

Animals↗

PubMed1988

Mechanisms of potentiation of antitumor activity of 5-fluoro-2'-deoxyuridine in the adenocarcinoma 755 system by guanosine 5'-monophosphate.

The effect of guanosine 5'-monophosphate (GMP) on the antitumor activity of 5-fluoro-2'-deoxyuridine (FdUrd) was investigated by using a solid tumor, adenocarcinoma 755. FdUrd only slightly inhibited the tumor growth even at the maximum tolerated dos (ILS,6%). GMP at 300 mg/kg/day markedly potentiated the inhibition of tumor growth by FdUrd (ILS, 61%). When tumor-bearing mice were treated with the combination of 3H-FdUrd and GMP, 3H-FdUrd was significantly incorporated into tumor RNA as compared to the mice not given GMP, although the 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) level in the tumor in the combination with GMP was decreased. The increased incorporation of 3H-FdUrd into RNA ([FUra]RNA) of the tumor was due to an increased level of FUra in plasma and tumor. On the other hand, incorporation of 3H-FdUrd into the RNA of the small intestine, which is one of main target tissues of FUra toxicity, was not increased. Thus, the potentiating effect of GMP on the antitumor activity of FdUrd is apparently due to the specifically increased FdUrd and FUra levels in the tumor. The combination with GMP caused marked incorporation of 3H-FdUrd into RNA in the tumor but uptake of 3H-FdUrd into RNA in the small intestine was not increased. These results suggest that GMP can potentiate the antitumor activity of FdUrd without increasing gastro-intestinal toxicity.

Adenocarcinoma↗

PubMed1987

The different effects of recombinant human tumor necrosis factor on rat fibrosarcoma sublines.

The antitumor effect of recombinant human tumor necrosis factor (rH-TNF) on two clones of rat fibrosarcoma with different metastatic potential to lymph nodes was examined. The colony formation of clone A, which has high metastatic potential, was completely inhibited by continuous exposure to rH-TNF at 50 U/ml. In contrast, colony formation of clone G, which has low metastatic potential, was not inhibited by high concentrations of rH-TNF (10,000 U/ml). The inhibitory effect of rH-TNF on colony formation by clone A was also observed with a 1-h exposure to rH-TNF. This effect was time and concentration dependent, as determined by the colony assay, 3H-thymidine uptake assay, and 51Cr-release assay. 3H-thymidine and 3H-uridine uptake per cell of clone A exposed to rH-TNF was not decreased. This suggests that the mechanisms of the antitumor effect of rH-TNF were not due to inhibition of DNA and RNA synthesis of tumor cells. In vivo growth and lymph node metastases of clone A inoculated i.p. to Donryu strain rats were completely suppressed by 14 consecutive i.p. injections of 10(5) or 10(6) U/kg per day of rH-TNF. On the other hand the growth of clone G was not influenced by rH-TNF administration.

Animals↗

PubMed1987

Elevation of plasma levels of fluorinated pyrimidines by guanosine 5'-monophosphate.

The plasma concentration of 5-fluorouracil (FUra) following the i.v. administration of FUra and guanosine 5'-monophosphate (GMP) or guanosine 5'-triphosphate (GTP) was markedly elevated. These values were more than 5-fold higher than those obtained with FUra alone over 60 min after administration. The elevation of plasma levels corresponded to the dose of GMP. Higher levels of FUra were maintained in the plasma after injection of inosine or inosine 5'-monophosphate in combination with FUra than after FUra alone, but they were lower than those induced by GMP or GTP. Moreover, plasma levels of two other fluorinated pyrimidines, 5'-deoxy-5-fluorouridine (DFUR) and 5-fluoro-2'-deoxycytidine (FdCyd), were also elevated by GMP. The combination of DFUR and GMP resulted in higher plasma levels of DFUR itself and FUra (12- and 10-fold, respectively, 30 min after treatment). After administration of FdCyd plus GMP, the plasma levels of FdCyd, 5-fluoro-2'-deoxyuridine, which is converted from FdCyd by cytidine deaminase, and FUra were 2-, 6-, and 7-fold higher, respectively, than those after FdCyd alone 30 min after treatment. Thus, GMP is the most effective compound for the maintenance of high plasma levels of fluorinated pyrimidines.

Animals↗

PubMed1987

Potentiation of the chemotherapeutic action of 5'-deoxy-5-fluorouridine in combination with guanosine and related compounds.

The effect of inosine, guanosine, and guanosine 5'-monophosphate (GMP) on the antitumor activity of 5'-deoxy-5-fluorouridine (5'-DFUR) was investigated using P388 leukemia and P815 mastocytoma. The antitumor activity of 5'-DFUR was markedly enhanced by coadministration of inosine or guanosine. The increase in lifespan (ILS) of mice treated with 5'-DFUR was augmented by the combination with guanosine or inosine in a dose-dependent fashion, and the maximum ILS was about 160% with the combination, while that in the case of 5'-DFUR alone was only 48% in the P388 leukemia system. The therapeutic ratio (dose at ILSmax/dose at ILS30) of the combination with guanosine or inosine was 333 and 136, respectively, whereas that of 5'-DFUR alone was 3.6. GMP also markedly potentiated the antitumor activity of 5'-DFUR in both P388 leukemia and P815 mastocytoma systems, just as it potentiated the activity of 5-fluorouracil in the latter system. The uric acid level in the serum was elevated after IP injection of guanosine or inosine but the value was much lower in the case of guanosine than in inosine.

Animals↗