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Biomedical subjects

K Naganuma

Publications and source records attributed to K Naganuma.

At least 55 records · Page 3Linked to original sources
PubMed1984

Establishment of human KB cells resistant to 1-beta-D-arabinofuranosylcytosine, and mechanisms of cellular resistance in isolated clones.

A subline of human KB cells that was resistant to 1-beta-D-arabinofuranosylcytosine (ara-C) was established by continuous exposure of the cells to increasing concentrations of ara-C. Thirteen resistant clones were isolated from the resistant subline (KB/ara-C). KB/ara-C showed 1,300-fold higher resistance than the parent KB cells to ara-C; the most resistant clones, clones 7 and 10, showed 1,330-fold higher resistance. In the absence of ara-C, the resistance of the parent KB/ara-C cells was stable for at least 14 weeks, whereas that of clone 7 was stable for 10 weeks, but was slightly less after 14 weeks. The ara-C kinase and ara-C deaminase activities of the 13 clones and the cellular uptake of ara-C by several clones were measured. In general the clones showed decreased deoxycytidine kinase activity and decreased cellular uptake of ara-C. Most clones had higher cytidine deaminase activity than KB cells, but some had activity similar to that of the KB cells. A clear inverse relationship was found between the ara-C sensitivity of the clones and their kinase activity, but not their deaminase activity or their ara-C uptake. These results clearly demonstrate that a major mechanism of ara-C resistance of these human KB cells was a decrease in the activity of the ara-C activating enzyme deoxycytidine kinase. The parent KB/ara-C cells showed no clear cross-resistance to various antitumor agents other than an ara-C derivative, including metabolic inhibitors, alkylating agents, DNA binders and mitotic spindle poisons.

Antineoplastic Agents↗
PubMed1984

Antitumor effects and pharmacology of orally administered N4-palmitoyl-1-beta-D-arabinofuranosylcytosine in mice.

The antitumor activity and the pharmacological fate of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (N4-palmitoyl-ara-C) administered p.o. were examined in mice and were compared with those of the parent compound 1-beta-D-arabinofuranosylcytosine (ara-C). N4-Palmitoyl-ara-C administered p.o. showed chemotherapeutic effects superior to those of ara-C when used against P388 leukemia, L1210 leukemia, mammary adenocarcinoma 755, and colon 38 adenocarcinoma. The derivative also inhibited the spontaneous pulmonary metastasis of s.c.-inoculated Lewis lung carcinoma more efficiently than did ara-C. After a single p.o. injection of a suspension of N4-palmitoyl-[2-14C]ara-C at a therapeutic dose of 350 mu/kg, a high concentration of the drug was found in the liver, lung, and plasma of portal venous blood. The level of the drug in other tissues and peripheral plasma was rather low. The two main metabolites, identified as ara-C and 1-beta-D-arabinofuranosyluracil, were found in plasma and various tissues. Plasma ara-C concentration was maintained for at least 6 hr in the range of 2.3 to 5.1 nmol/ml after p.o. administration of N4-palmitoyl-ara-C (350 mu/kg). On the other hand, when an equimolar amount of ara-C was given, the plasma levels of the drug decreased rapidly; from 2 to 6 hr after administration, the level (1.0 to 4.1 nmol/ml) was less than that obtained with N4-palmitoyl-ara-C. These results suggested that N4-palmitoyl-ara-C administered p.o. is absorbed as an intact form from the gastrointestinal tract and that the absorbed compound is the depot form of ara-C, releasing ara-C over a prolonged period of time.

Adenocarcinoma↗
PubMed1984

Metastasis after intravenous inoculation of highly metastatic variants of mouse tumors and the effects of several antitumor drugs on the tumors.

Tumor metastasis was examined after iv inoculation of highly metastatic variants of mouse tumors. Highly metastatic variants, B16-F10 and B16-BL6, of B16 melanoma origin and colon 26 NL-17 of colon adenocarcinoma 26 origin were used in the experiments. Formation of pulmonary metastasis was influenced by the mouse strain and age. Based on the results, experimental metastasis systems of these tumors were established, and the effects of chemotherapeutic agents were examined. 5-Fluorouracil and adriamycin were significantly effective for the suppression of pulmonary metastasis. The degrees of suppression of metastasis by these drugs were different with different tumor variants, but the sensitivity of the metastasis to the drug was similar to that of the parent tumor. Several aspects of the chemotherapy of metastasis are discussed.

Adenocarcinoma↗
PubMed1984

Isolation and characterization of highly and rarely metastatic clones from murine colon adenocarcinoma 26.

Three typical metastatic clones, designated N-1, N-4, and N-5, were isolated in vitro from a murine colon adenocarcinoma 26 cell line (Colon 26). The incidence of spontaneous metastasis was highest in N-4 (85%), moderate in N-5 and Colon 26 (50 and 53%, respectively) and lowest in N-1 (0%). The major target organ of metastasis was the lung. Among the clones, N-4 showed higher lung colonizing potential after intravenous inoculation, higher tumorigenicity and higher saturation density in culture. Cell-surface analysis of cloned cells by 125I-labeled lectins revealed significant reduction of the number of concanavalin A (Con A)-binding sites in highly metastatic N-4 cells. In sodium dodecyl sulfate-slab gel analysis of cellular glycoproteins, a 94,000-dalton component, which is reactive to Con A, was more intensely observed in N-1 as compared with other clones and parental Colon 26. These clones could provide a new model for the study of metastasis of colon carcinoma.

Adenocarcinoma↗
PubMed1983

Characterization of metastatic clones derived from a metastatic variant of mouse colon adenocarcinoma 26.

A spontaneously metastatic variant (P-26-select) was selected from the murine colon adenocarcinoma 26 after repeated (26 times) cyclic in vivo passage of tumor cells from the lungs of mice bearing s.c. tumors. Clones were established from the cultured P-26-select cell line. These clones, the parent [P-no-select (culture cell line of colon 26 without in vivo selection)] and the metastatic variant (P-26-select) were then studied using three different assays to determine their metastatic potential. These assays included experimental metastasis, spontaneous metastasis from a nonresected s.c. growing tumor, and spontaneous metastasis following the resection of a primary footpad tumor. In general, there was an agreement among the results of these three assays of metastases, i.e., if a variant was spontaneously metastatic, it was also metastatic in the other assays of metastases. However, some experimentally metastatic clones did not necessarily show a high spontaneous metastatic potential to the lung. These results might indicate that the metastatic variant (P-26-select) is populated by spontaneously metastatic clones and also by clones which possess a propensity to metastasize experimentally. The morphology and growth properties of the clones were compared also.

Adenocarcinoma↗
PubMed1983

Promotion by verapamil of vincristine responsiveness in tumor cell lines inherently resistant to the drug.

Cultured cell lines LL, B16, C26, and C38 established from mouse solid tumors of Lewis lung carcinoma, B16 melanoma, and colon adenocarcinomas 26 and 38, respectively, showed inherently different resistance to vincristine (VCR) in vitro. The inherent resistance to VCR of these cell lines was related to the ability of the cells to accumulate VCR. Verapamil, a calcium antagonist with coronary vasodilator activity, enhanced the cytotoxicity of VCR against these cell lines depending upon their susceptibility to VCR. C26 cells, the most resistant, became the most susceptible to VCR with a nontoxic dose of verapamil. A 12-fold increase in VCR cytotoxicity occurred. Only a 2.5-fold increase in VCR cytotoxicity was observed for B16 cells, the most sensitive cells. VCR cytotoxicity against each cell line reached almost the same level by verapamil (2.2 to 6.6 microM). Thus, the inherent resistance to VCR among the tumor lines was circumvented. Verapamil enhanced the cellular accumulation of VCR. A 3- to 4-fold increase in cellular VCR occurred in C26 cells, while approximately a 2-fold increase was observed for B16 and LL cells. A similar rate of enhancement was observed for both bound and free VCR, indicating that verapamil does not enhance the affinity of VCR to tubulin. Verapamil inhibited the outward transport of VCR from the cells. The most prominent inhibition was observed for C26 cells. Circumvention of inherent resistance of tumor cells to VCR by verapamil could be attained through an enhanced cellular accumulation of VCR in each of the tumor cells. The enhancement of VCR cytotoxicity and circumvention of inherent VCR resistance by verapamil could be explained by the cellular concentration of VCR, and also it might be related to the extent of VCR binding to tubulin in the cell. The chemotherapeutic effect of VCR is significantly enhanced by verapamil in colon adenocarcinoma 26-bearing mice.

Adenocarcinoma↗
PubMed1982

[Effect of dopamine intracerebrally injected by the Valzelli method on methamphetamine-stereotypy and hypermotility].

In this investigation, the effect of methamphetamine (MAPT) was examined on stereotyped licking and biting and locomotor activity in reserpinized rats which were administered dopamine (DA) intracerebrally. Twenty-four hours after the treatment of reserpine (RE, 1.25 mg/kg ip) or 0.9% saline solution. Wistar male rats received DA (300 micrograms/rat ic) or 0.9% saline solution (5 microliters/rat ic) by Valzelli's method and then 10 min later MAPT (3 mg/kg or 10 mg/kg ip) Stereotyped biting was induced by each dose of MAPT in reserpinized rats. This was suppressed, however, in reserpinized rats given DA. Stereotyped licking was induced by MAPT (10 mg/kg ip) in saline-treated rats. This score did not differ in comparison with the case given DA. Hypermotility was shown by each dose of MAPT in reserpinized and saline-treated rats. This was particularly potentiated in reserpinized rats given DA before the MAPT (10 mg/kg ip), but not any cases of saline-treated rats combined with DA. It is suggested that MAPT-induced stereotyped licking and biting are suppressed in reserpinized rats given DA in a high dose while MAPT-induced hypermotility is potentiated in rats treated as above.

Animals↗
PubMed1981

Inhibition of lymph node metastasis of P388 leukemia by bestatin in mice.

Bestatin, a chemically defined immunostimulant of low molecular weight, suppressed the gradually-occurring lymph node metastasis of P388 leukemia in CDF1 mice when administered i.p. at the doses of 1 approximately 30 micrograms/mouse. It could not, however, suppress the established large metastasis of P388 leukemia. Lymph node cells isolated from the mice given bestatin i.p. at 1 and 30 microgram/mouse showed cytostatic activity against P388 leukemic cells in vitro than those from the untreated mice.

Animals↗
PubMed1980

Inhibition of murine colon adenocarcinomas and Lewis lung carcinoma by 1-hexylcarbamoyl-5-fluorouracil.

1-Hexylcarbamoyl-5-fluorouracil (HCFU) and its parent compound 5-fluorouracil (5-FU) were tested PO for antitumor activity against mouse colon adenocarcinoma 26 (colon 26), colon adenocarcinoma 38 (colon 38), and Lewis lung carcinoma. The drugs were given orally at 2--4 days intervals for a total of ten doses. 5-FU was moderately active against colons 26 and 38 but not against Lewis lung carcinoma. In this treatment regimen the most impressive antitumor activity was obtained with HCFU against colons 26 and 38, especially colon 38 tumor. At 300 mg HCFU/kg, one out of seven mice inoculated with colon 26 and five out of ten mice inoculated with colon 38 became tumor-free. HCFU, however, was marginally effective in the prolongation of survival time of mice bearing Lewis lung carcinoma. 5-FU is approximately twice as active as HCFU against cultured cell lines from colon 26, colon 38, and Lewis lung carcinoma. Lewis lung carcinoma cells were most sensitive against HCFU, which is in contrast to the results obtained in the in vivo experiment. The IC50 value of HCFU against Lewis lung carcinoma cells was approximately half that against colon 26 and colon 38 cells. This higher sensitivity of Lewis lung cells against HCFU could be explained by the higher cellular uptake of the drug.

Adenocarcinoma↗
PubMed1980

Antitumor efficacies of aclacinomycin A by oral administration.

For the purpose of seeking a possible base for the oral clinical application of an anthracycline antibiotic, aclacinomycin A (ACM), ACM was given orally to the mice bearing Lewis lung carcinoma, colon adenocarcinomas 26 and 38, and compared with the effect of adriamycin (ADM). Oral administration of ACM at 5 or 10 mg/kg for 10 time suppressed the growth of Lewis lung carcinoma. There was no significant difference in survival times of the tumor-bearing mice given ACM orally at various dosages tested. ADM was not effective orally as long as the antitumor effect was examined at the dose levels tested. However, significant increase in the survival time of the mice implanted s.c. with colon adenocarcinoma 26 or 38 was noted for oral administration of ACM at 5-10 mg/kg for 10 times. Ths is, at 10 mg/kg of ACM, T/C% was 187% against colon 26 and 141% against colon 38, respectively. ADM, was not effective against these mouse tumors when given orally. Clinical application of ACM by oral administration, however, will need further studied including preclinical pharmacology, drug formulation and others.

Aclarubicin↗
PubMed1980

Lymph node metastasis and effects of 1-beta-D-arabinofuranosylcytosine, 5-fluorouracil, and their lipophilic derivatives in an experimental model system using P388 leukemia.

Mouse P388 leukemic cells inoculated into the right forefootpad metastasized primarily to the right axillary lymph node. No significant metastasis to other lymph nodes or organs was detected on Day 12 after the inoculation of 10(6) P388 cells in the forefootpad, except that a lesser extent of metastasis was observed in some cases in the right inguinal lymph node, liver, and spleen. A quantitative estimation of metastasis in the axillary lymph node was accomplished by transferring the lymph node i.p. to the recipient mice (bioassay method). The metastasis of P388 cells to the axillary lymph node occurred linearly depending on the elapse of time after inoculation. In studying the chemotherapeutic effect on lymph node metastasis, two experimental models were established. Model 1, 10(6) P388 cells were inoculated into the right forefootpad, and drug was administered thereafter. The right axillary lymph node was removed on Day 8, and the extent of inhibition of lymph node metastasis was estimated by the bioassay method. In Model 2, P388 cells were inoculated, and the right forelimb including original tumor was amputated on Day 6 when the metastasis had already been established. The drug was given thereafter, and the extent of inhibition of metastasis was estimated on Day 12 by the bioassay method. In this experimental system, a lipophilic derivative N4-behenoyl-1-beta-D-arabinofuranosylcytosine was more effective than its parent compound 1-beta-D-arabinofuranosylcytosine; however, 5-fluorouracil was found to be more potent than its lipophilic derivative ftorafur for the inhibition of lymph node metastasis, suggesting an existence of various pharmacokinetic factors for the inhibition of lymph node metastasis.

Animals↗