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Biomedical subjects

M Iigo

Publications and source records attributed to M Iigo.

At least 91 records · Page 5Linked to original sources
PubMed1987

Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil and ftorafur against adenocarcinoma 755 in mice.

When combined with bromovinyldeoxyuridine (BVdUrd), 5-fluorouracil (FUra) brought about a significant reduction in the growth of adenocarcinoma 755 tumors in mice, at doses at which either drug used alone (BVdUrd: 100 mg/kg) did not effect an appreciable antitumor activity. BVdUrd also increased the toxicity of FUra for the hosts but not commensurately with its enhancing effect on the antitumor activity of FUra. BVdUrd also potentiated the antitumor activity of ftorafur, so that doses of ftorafur (50 or 100 mg/kg) which by themselves did not cause a significant reduction in tumor growth became markedly effective when combined with BVdUrd at a dose as low as 10 mg/kg. For some combinations of BVdUrd with FUra, the antitumor potency was further enhanced by the administration of L-cysteine (300 mg/kg).

Adenocarcinoma↗
PubMed1987

Mechanism of potentiation of antitumor activity of 5-fluorouracil by guanine ribonucleotides against adenocarcinoma 755.

The effect of various guanine ribonucleotides on the antitumor activity of 5-fluorouracil (FUra) was investigated by its action on adenocarcinoma 755. 5'-GDP and 5'-GMP were both equally effective in potentiating the antitumor activity of FUra without increasing toxicity. 5'-GTP and 5'-IMP also potentiated the activity but not as much as 5'-GMP. 2'-GMP and 3'-GMP did not enhance the antitumor activity. In contrast, cGMP antagonized the effects of FUra. The incorporation of 3H-labeled FUra into RNA or DNA showed there was no obvious association between the incorporation and antitumor activity after any treatment with guanine ribonucleotides. The combination of FUra and 5'-GMP produced the greatest inhibition of RNA synthesis. The combination of FUra and 2'-GMP had no effect on RNA synthesis. The inhibition of RNA synthesis may be the result of decreased pyrimidine pool size and increased incorporation of FUra into RNA. Potentiation of the antitumor activity of FUra by 5'-GMP was reversed by the injection of cytidine. Moreover, the combination of 5-fluorocytidine (FCyd) and 5'-GMP showed greater antitumor activity than FCyd alone. These results indicate that a decreased CTP pool potentiates the antitumor activity of FUra. Thus, 5'-GMP or 5'-GDP strongly enhanced the antitumor activity of FUra, and the potentiation resulted from the inhibition of RNA synthesis caused by reduction of the CTP and UTP pool sizes and increased incorporation of FUra into RNA.

Adenocarcinoma↗
PubMed1987

[Direct and indirect antitumor effect of murine recombinant interferons].

The antitumor effects of murine recombinant interferons (beta) and (gamma) against B-16 melanoma and B16-F10 melanoma were examined. In a pharmacokinetic study, intraperitoneal injection of Mu-rIFN (gamma) produced higher and longer detectable IFN activity than administration of Mu-rIFN (beta) in both plasma and organs. In clonogenic assay, Mu-rIFN (gamma) at 1,000 units/ml showed 80% inhibition of colonies of B16-F10 melanoma. However, Mu-rIFN (beta) hardly inhibited the colony formation of B16-F10 melanoma. Furthermore, both IFNs had different characteristics from each other in the augmentation of NK cell and macrophage activities. In the experimental metastasis of B-16 melanoma, the inhibitory effect of Mu-rIFN (beta) on the pulmonary metastasis was mediated by the host defense mechanism, and NK cells and macrophages were important for the inhibition. Mu-rIFN (gamma) showed a stronger effect against B16-F10 melanoma in the inhibition of the growth of sc implanted tumor and artificial metastasis.

Animals↗
PubMed1987

The antitumor potency of oral tegafur against adenocarcinoma 755 in mice is markedly enhanced by oral (E)-5-(2-bromovinyl)-2'-deoxyuridine.

A significant inhibition of the growth of adenocarcinoma 755 tumors in BDF1 mice was effected by oral tegafur (FT) in combination with oral (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd), at doses at which neither drug used alone had antitumor activity. The maximum inhibition of tumor growth (97%) was achieved by using a combination of 50 mg FT/kg with 10 mg BVdUrd/kg but, even at a dose as low as 1 mg BVdUrd/kg, the antitumor potency of FT was enhanced. The effect which BVdUrd has on the antitumor potency of FT is apparently due to inhibitory action by bromovinyluracil, the phosphorolytic product of BVdUrd, on the degradation of 5-fluorouracil, the oxidative product of FT, by dihydrothymine dehydrogenase.

Adenocarcinoma↗
PubMed1987

Synthesis and antitumor activity of 1- or 3-(alpha-hetero substituted)alkyl-5-fluorouracil derivatives.

Two classes of 5-fluorouracil (5-FU) derivatives were prepared from 1,3-bis(hydroxymethyl)-5-fluorouracil (1). The first group was obtained by the direct esterification of 1 with various acids. The second one was derived by the nucleophilic substitution of N-(chloromethyl)-5-FUs, which were easily prepared by halogenation of 1, with hetero nucleophiles. The antitumor activities of the prepared compounds were examined against Leukemia L1210 and the results were compared with that of 1-hexylcarbamoyl-5-fluorouracil (HCFU, Carmofur).

Animals↗
PubMed1986

Potentiation of the chemotherapeutic action of tegafur against solid adenocarcinoma 755 by combination with L-cystine.

The chemotherapeutic action of tegafur (FT) against adenocarcinoma 755 in mice was markedly potentiated by oral administration of L-cysteine and L-cystine without increasing its toxicity. In particular, the combination of FT at 200 mg/kg per day (maximum dose) and 1000 mg/kg per day of L-cystine markedly inhibited tumor growth. The dose ratio of L-cysteine or L-cystine to FT needs 5 by weight to potentiate the antitumor activity of FT. The antitumor activity of 5-fluorouracil (FU) was slightly, but not significantly, increased by L-cysteine. The total concentration of FT in the plasma and the tumor when it was given in combination with L-cystine was significantly increased when compared with FT alone 1 h after oral administration. The FU level in the plasma after administration of the combination of FT and L-cystine was three times higher than that after FT alone, and the FU level in the tumor after treatment with the combination of FT and L-cystine was also higher (about 20%) than that after FT alone. This significant increase in FT and FU levels in the plasma and the tumor may be related to the potentiation of the antitumor activity of FT by L-cystine.

Adenocarcinoma↗
PubMed1986

Antitumor activity of derivatives of neplanocin A in vivo and in vitro.

Neplanocin A is a cyclopentenyl analog of adenosine which has been isolated from the culture filtrate of Ampullariella reqularis. Antitumor activity of twenty three derivatives of neplanocin A was examined against L1210, sarcoma 180 and L5178Y. Neplanocin A showed a marked inhibition of growth of L1210 in vivo. Other derivatives which had a 2' or 3'-substituted cyclopentene group showed weak cytotoxicity against L5178Y cells in vitro. Neplanocin A inhibited the biosynthesis of ribonucleic acid (RNA) and protein, while 6-chloroneplanocin A, a new active derivative, showed a specific inhibition of only RNA synthesis. The two hydroxy groups in the cyclopentene moiety with a ribose type structure are important for marked antitumor activity.

Adenosine↗
PubMed1986

Inhibitory effect of murine recombinant interferon (beta) on the pulmonary metastasis of B-16 melanoma.

The antitumor effect of murine recombinant interferon (beta) [Mu-rIFN(beta)] was examined on artificial metastasis of B-16 melanoma in C57BL/6 mice. The numbers of pulmonary nodules were significantly decreased to 16.7 +/- 4.7 (P less than 0.01), 9.5 +/- 4.2 (P less than 0.01), 7.1 +/- 5.6 (P less than 0.01) in mice given 20,000 units of Mu-rIFN(beta) intraperitoneally (ip) 24, 6, and 3 hr before intravenous tumor inoculation, respectively, compared with the control group of mice (57.1 +/- 1.4), if B-16 melanoma cells (5 X 10(5] were intravenously injected 28 days before the experiment. In mice given 20,000 units of Mu-rIFN(beta) ip 24, 6, and 3 hr before the experiment, the natural killer (NK) activities of spleen cells against YAC-1 cells were elevated to 45.5 +/- 6.1%, 53.7 +/- 3.4%, 43.2 +/- 6.5%, respectively, compared with NK activities in control mice (20.3 +/- 3.1%). Similarly, NK activities against B-16 melanoma cells were also elevated in mice given Mu-rIFN(beta). Pretreatment with anti-asialo GM1 antibody and carrageenan reduced the inhibitory effect of Mu-rIFN(beta) on the pulmonary metastasis. In vitro colony inhibition of more than 50% was not observed even if B-16 melanoma cells were incubated with 100,000 units/ml of Mu-rIFN(beta). From these results, it can be concluded that the inhibition of pulmonary metastasis by Mu-rIFN(beta) is mediated via host defense mechanisms and that NK cells and macrophages are both important for the inhibition.

Animals↗
PubMed1985

Synergistic antitumor effect of fluoropyrimidines and polyinosinic-polycytidylic acid against L1210 leukemia.

The effect of polyriboinosinic X polyribocytidylic acid [poly(I) X poly(C)] on the antitumor activity of 5-fluorouracil (FUra) and 5-fluorouridine (FUrd) was evaluated in mice bearing L1210 leukemia. Coadministration intravenously of poly(I) X poly(C) and either FUra or FUrd on days 1,5, and 9 to mice bearing L1210 leukemia implanted subcutaneously resulted in a 40% greater increase in life span at the optimal antitumor dose versus FUra and FUrd alone. This effect appeared to result from greater host tolerance of a dose of FUra or FUrd which would otherwise be cytotoxic. The protective effect of poly(I) X poly(C) was also evident in non-tumor-bearing mice, as well as following administration of drug intraperitoneally to mice bearing the tumor implanted intraperitoneally. FUrd incorporation into RNA in the spleen, bone marrow, and small intestine revealed little or no changes after coadministration of poly(I) X poly(C). (2', 5')Oligo(A) synthetase activity, an indication of interferon activity, was markedly depressed in the spleen and bone marrow following treatment with FUrd; however, poly(I) X poly(C) administered together with FUrd returned (2', 5')oligo(A) synthetase activity to normal levels. These data indicate that poly(I) X poly(C) ameliorates the host toxicity of fluoropyrimidines, possibly via an interferon-mediated effect, and thereby results in enhanced therapeutic efficacy of the antimetabolite as an antitumor agent.

2',5'-Oligoadenylate Synthetase↗
PubMed1985

Antagonistic effect of polyinosinic-polycytidylic acid on the cell lethality produced by 5-fluorouracil in human colon carcinoma cells in vitro.

The effect of polyinosinic X polycytidylic acid [poly(I) X poly(C)] on the cell lethality produced by 5-fluorouracil [FUra] and 5-fluorouridine [FUrd] was examined in human colon carcinoma cell line HT-29. Pretreatment of cells with poly(I) X poly(C) as well as during exposure to FUra or FUrd resulted in antagonism of the cell lethality generated by the fluoropyrimidines. Antagonism of FUra cytotoxicity was also produced by the 2'-O-methylated analogue, polyinosinic X poly-2'-O-methylcytidylic acid, but not by the individual single-stranded polynucleotides or by the component mononucleotides, cytidine 5'-phosphate and inosine 5'-phosphate. In contrast, cytidine 5'-phosphate blocked the toxicity of FUrd. The antagonism by poly(I) X poly(C) of FUra and FUrd cytotoxicity was related to the inhibition of their metabolism to fluorouridine triphosphate and their incorporation into RNA and not to inhibition of the synthesis of RNA. Antibodies to leukocyte and fibroblast interferons did not reverse the antagonistic activity of poly(I) X poly(C). These results indicate that poly(I) X poly(C) may be interfering with the transport and/or initial metabolism of FUra and FUrd to fluorouridine monophosphate which is independent of the ability of the double-stranded RNA to induce interferon.

Cell Survival↗
PubMed1984

Effect of guanosine on antitumor activity of fluorinated pyrimidines against P 388 leukemia.

The antitumor activity of the fluorinated pyrimidines 5-fluorouracil (FUra), 5-fluorouridine (FUrd), and 5-fluoro-2'-deoxyuridine (FdUrd) against P388 leukemia was markedly potentiated by the addition of guanosine (Guo), resulting in therapeutic synergism. Any combination of FUra at 1-20 mg/kg, FUrd at 0.3-1 mg/kg, or FdUrd at 1-100 mg/kg with Guo at 100 mg/kg significantly potentiated the activity of FUra, FUrd, or FdUrd, respectively. The potentiation of these fluorinated pyrimidines by guanosine was abolished by the simultaneous administration of cytidine or uridine, but not of thymidine. In particular, cytidine was the strongest inhibitor of antitumor activity of these fluorinated pyrimidines, alone and in combination with guanosine. To obtain more effective treatment with the combination of various fluorinated pyrimidines and Guo, the influence of the molar ratios of Guo to the fluorinated pyrimidines on the antitumor activity against P388 leukemia was investigated. The increase in life-span became more pronounced with increasing molar ratios. The optimal molar ratios of Guo/FUra, Guo/FUrd, and Guo/FdUrd were more than 5, 100, and 5, respectively.

Animals↗
PubMed1984

Influence of molar ratio on the combination effect of 5-fluorouracil with guanosine 5'-monophosphate on P388 and L1210 leukemias.

To obtain more effective treatment with the combination of 5-fluorouracil (FUra) and guanosine 5'-monophosphate (GMP), the influence of the time interval between FUra and GMP administration and of the molar ratio of GMP to FUra on the effect on P388 murine leukemia were investigated. The antitumor activity of FUra was significantly potentiated when GMP was administered either 0-60 min before or 5 min after FUra. The potentiated increase in lifespan (ILS) was almost the same as after simultaneous injection of the two agents. Coadministration of FUra and GMP increased the antitumor activity as compared with the respective dose of FUra alone in a treatment schedule of either day 1 only or days 1-9. The multiple-dose regimen (days 1-9) was more effective than a single high-dose regimen, and a GMP/FUra molar ratio of 4 seems to achieve the best therapeutic results against P388 leukemia. Daily simultaneous administration of FUra and GMP on days 1-9 also resulted in a significant increase in the antitumor activity against L1210 Leukemia as compared with FUra alone.

Animals↗
PubMed1983

Characterization and analysis of oncofetal tRNA and its possible application for cancer diagnosis and therapy.

We determined the primary structures of various tumor-specific tRNAs as well as of their normal counterparts by postlabeling RNA-sequencing procedures. The results clearly indicated that tumor-specific tRNAs are mostly formed by undermodification of hypermodified nucleosides located in the anticodon loop: no new tRNA transcripts have so far been found in tumor cells. Among the modified nucleosides affected by tumorigenesis, queuosine and Y base are the most interesting. In various tumor tRNAPhe species, hydroxy Y base located next to the anticodon is undermodified to form hypomodified hydroxy Y base lacking methyl and carboxymethyl groups. This Y base analog should be a good marker for analyzing the state of cancer cells. Queuosine, located in the first position of the anticodon, is partly or completely replaced by guanosine in all tumor cells tested so far. The amount of G-tRNA decreased markedly when the cells differentiated into mature erythroid cells, with concomitant increase of Q-tRNA. This indicates that the presence of G-tRNA is closely related to the state of the cells, not merely to the fast growth rate of tumor cells. The enzyme tRNA-guanine transglycosylase, which is a key enzyme in biosynthesis of queuosine in tRNA (inserting Q base into tRNA by a transglycosylase reaction), is active in both tumor cells and normal cells. Administration of chemically synthesized Q base to tumor-bearing mice resulted in complete conversion of G-tRNA to Q-tRNA in tumor cells, indicating that exogenously added Q base is effectively incorporated into G-tRNA. Various Q base analogs that can be used as substrates for tRNA-guanine transglycosylase were synthesized chemically. These compounds may be used for clinical cancer diagnosis, since they should be incorporated selectively into tRNA in tumor cells. In addition to use as cancer chemotherapeutic reagents, it should be possible to develop new Q base analogs that induce miscoding or blocking of protein synthesis after insertion into G-tRNA.

Animals↗