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Biomedical subjects

T Tsuruo

Publications and source records attributed to T Tsuruo.

At least 469 records · Page 26Linked to original sources
PubMed1986

Rhizoxin, a macrocyclic lactone antibiotic, as a new antitumor agent against human and murine tumor cells and their vincristine-resistant sublines.

Rhizoxin, isolated from a plant pathogenic fungus which causes rice seedling blight, inhibits the mitosis of the tumor cells in a manner similar to that of Vinca alkaloids as revealed by morphological study and flow cytometry analysis. This new 16-membered macrocyclic lactone showed similar chemotherapeutic effects to those of vincristine against L1210 and P388 leukemia-bearing mice. The drug is also effective against B16 melanoma inoculated i.p. or s.c. Rhizoxin, in contrast to the ansamacrolide, maytansine, was effective against human and murine tumor cells resistant to vincristine and Adriamycin in vitro and in vivo. A maximum 60% increase in life span was obtained in mice inoculated with P388 leukemia resistant to vincristine. Rhizoxin showed greater cytotoxicity in cultured tumor cells than did vincristine. Rhizoxin seems to bear consideration for further development as a new chemotherapeutic agent.

Animals↗
PubMed1985

Treatment of children with refractory acute lymphocytic leukemia with vincristine and diltiazem.

Six children with refractory acute lymphocytic leukemia were treated with vincristine combined with diltiazem. In four of five children who took the drug as scheduled, a cytolytic effect was observed. One child showed massive cell destruction which caused hyperuricemic nephropathy. The only adverse effect was atrioventricular block in two children, which was completely reversible. Increased neurotoxicity was not observed in any child.

Benzazepines↗
PubMed1985

Potentiation of antitumor agents by calcium channel blockers with special reference to cross-resistance patterns.

The calcium channel blockers verapamil, diltiazem, nicardipine, and niludipine potentiated the antitumor activities of mitotic poison antitumor agents, such as vincristine, vinblastine, vindesine, VP16-213, and taxol in P388 leukemia cells resistant to vincristine. The potentiating effect was generally dependent on the extent of cross-resistance seen in the cell line for these drugs. Calcium channel blockers also potentiate the antitumor activities of several DNA-interacting drugs, such as adriamycin, THP-adriamycin, daunomycin, aclacinomycin A, mitomycin C, actinomycin D, mitoxantrone, and nogalamycin derivatives in P388 leukemia resistant to adriamycin. Greater potentiation was observed for those antitumor agents to which the ADM-resistant cell line had become markedly cross-resistant, with the exception of the nogalamycin derivatives. Only a two-fold enhancement was observed for mitomycin C and aclacinomycin, as the cell line was only weakly cross-resistant to these agents. These results suggest the potential for therapeutic gain through the use of calcium channel blockers in combination with classic chemotherapeutic agents.

Animals↗
PubMed1985

Inhibition of spontaneous and experimental tumor metastasis by the calcium antagonist verapamil.

Verapamil, a calcium antagonist, inhibited both experimental (IV inoculation of tumor cells) and spontaneous metastasis (SC inoculation) of the highly metastatic B16 melanoma and colon adenocarcinoma 26 cell lines. Verapamil treatment resulted in a maximum 80% inhibition of metastases, the degree of inhibition varying among the different metastatic systems. Verapamil inhibited platelet aggregation induced by these tumor cell lines, the patterns of inhibition being different for B16 melanoma and colon adenocarcinoma. The inhibition of platelet aggregation induced by tumor cells is proposed as a mechanism by which the calcium antagonist exerts its antimetastatic effect. These results, together with our previous findings that calcium antagonists can increase the cytotoxicity of drugs in tumor cells with induced or inherent drug resistance by inhibiting outward transport of the drug, indicate that calcium antagonists have potential as a new class of adjuvant agents in the field of cancer chemotherapy.

Animals↗
PubMed1985

Synthesis and antitumor activity of tropolone derivatives. 2.

Structural requirement for antitumor activity of tropolone derivatives 2-4 was explored. Isochroman derivatives (6-17, 20, and 23) and alpha, alpha-disubstituted compounds 26-30 were synthesized and their antitumor activities were tested. These nontroponoid derivatives were all inactive, implying that a tropolone ring is essential for the activity. Several compounds related to the monotropolone analogue 3 were synthesized. Among them, 31-33 showed significant activity, but their potencies were considerably weaker than those of binary tropolone analogues 4.

Animals↗
PubMed1985

[Antitumor drug resistance and therapeutic approaches to reverse resistance].

Acquired multidrug resistance as well as innate drug resistance are directly related to ineffectiveness and failure of the cancer chemotherapy. The mechanisms of such resistance, especially those of innate resistance, have not been fully elucidated. Drug resistant tumor cells, however, usually bear biochemical changes which are related to resistance mechanisms. New modalities with high selectivity against resistant cells could, therefore, be possible if we could target these biochemical changes. Vincristine (VCR)-and adriamycin (ADM)-resistant tumor cells (pleiotropic drug resistant cells) usually show an enhanced outward transport of these antitumor agents, and they express unique glycoproteins in the plasma membrane. By targeting for these biochemical changes characteristic to the resistant tumor cells, we establish new modality which shows high selectivity against drug resistant tumor cells. In this review, I will describe genetic origin of drug resistance, biochemical mechanisms of drug resistance and reversal of drug resistance in tumor cells. The modality to utilize calcium channel blockers which inhibit the enhanced outward transport of VCR and ADM from resistant tumor cells will be reviewed.

Antineoplastic Agents↗
PubMed1985

Cure of mice bearing P388 leukemia by vincristine in combination with a calcium channel blocker.

Mice inoculated with P388 leukemia were treated initially with vincristine (VCR) at a dose of either 1.5 or 2.0 mg/kg. After 1 week, VCR alone (0.1 mg/kg) was given daily for ten treatments, but no mice were cured with this regimen. However, when the calcium channel blocker verapamil (75 mg/kg) was administered with VCR at 1.5 or 2.0 mg/kg, lifespans were prolonged and one of ten or six of ten mice were cured, respectively. As reported previously, verapamil renders less sensitive or resistant tumor cells susceptible to VCR by inhibiting the VCR efflux mechanism, especially in resistant cells. Therefore, verapamil in combination with VCR apparently can result in total cell kill under the conditions used.

Animals↗
PubMed1984

Synthesis and antitumor activity of tropolone derivatives.

Treatment of tropolones with benzaldehyde diethyl acetals gave monotropolone (12) and bistropolone (13) derivatives at the benzylic position, whereas the related 1-ethoxyisochroman and the diethyl acetals of crotonaldehyde and cinnamaldehyde gave only the monotropolone derivatives (5, 10, or 11). The monotropolone derivatives (5, 10, 11, and 12) had poor potency against P388 leukemia in mice, but the bistropolone derivatives (13 and 14) showed significant potency and prolongation of life.

Animals↗
PubMed1984

Adhesive properties of weakly and highly metastatic melanoma cell lines.

The aggregating properties of murine melanoma cell lines with low metastatic potential (B16-F1) and high metastatic potential (B16-F10 and B16-BL6) were compared. All three types of cells were found to possess Ca2+-dependent and Ca2+-independent intrinsic mechanisms for cell adhesion, though the extent of reaggregation varied in each mechanism. After trypsin treatment at around 1 microgram/ml, F10 and BL6 cells reaggregated in the presence of 1mM Ca2+ to a greater degree than F1 cells. F10 and BL6 cells were also more aggregative than F1 cells after dissociation with collagenase. The apparent adhesiveness of the cells was found to be dependent on both the manner of cell preparation for reaggregation and on the presence of external Ca2+ or serum factors. The results are discussed in relation to the mechanisms of tumor cell arrest with emphasis on the effect of extracellular factors on cell adhesiveness.

Animals↗
PubMed1984

Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells.

Quinidine, which has antiarrhythmic activity, greatly enhanced the cytotoxicity of vincristine (VCR) in tumor cells and especially in VCR-resistant sublines of P388 leukemia (P388/VCR) and human myelogenous leukemia. A nontoxic concentration of quinidine increased VCR cytotoxicity in these resistant tumor cells about 50 to 80 times, and the drug in combination with VCR could completely reverse VCR resistance of these cell lines. Quinidine also enhanced the cytotoxicity of Adriamycin, especially in the Adriamycin-resistant subline of P388 leukemia; this enhancement (8-fold) was less than that of VCR toxicity in the VCR-resistant tumor line. When administered daily for 10 days with VCR, quinidine at doses of 50 to 125 mg/kg significantly enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. Some other antiarrhythmic agents also showed similar effects in vitro, but these effects were considerably lower than that of quinidine. Quinidine increased the cellular levels of VCR and daunomycin in VCR-resistant sublines of mouse and human tumors and the ADM-resistant mouse tumor line in vitro, respectively. Quinidine also enhanced the cellular accumulation of VCR in P388/VCR cells in vivo. Thus, the therapeutic effect observed in P388/VCR-bearing mice might be due to the enhanced accumulation of VCR in P388/VCR cells by quinidine. The increase of cellular accumulation of VCR was partly explained by inhibition of efflux of VCR and daunomycin from the resistant tumor cells. The mechanism of this phenomenon is discussed in relation to previous findings on calcium channel blockers.

Animals↗
PubMed1984

Spontaneous metastasis of highly metastatic variants of mouse tumors and the effect of drugs on the metastasis.

Spontaneous metastasis of highly metastatic variants, B16 melanoma BL-6 and colon adenocarcinoma 26 NL-22, was examined. Tumor cells were inoculated into the right front footpad and the original tumors were removed by amputation of the forelimb at an appropriate time after tumor inoculation. Spontaneous lymph node and lung metastases occurred with B16 BL-6 and spontaneous lung metastasis occurred with NL-22. Analysis of the time-dependent formation of lymph node and lung metastases of BL-6 indicated that lung metastasis could be formed after the lymph node metastasis. Metastasis is influenced by the mouse strain, and both inbred and F1 hybrid mice of syngeneic origin could be used as host animals. By using these metastatic variants, two spontaneous metastasis systems were established. In order to evaluate the systems, the effects of 5-fluorouracil (5-FU) and adriamycin (ADM) were examined. 5-FU was effective against the metastases of both tumors, and ADM was moderately effective against B16 BL-6 metastasis.

Adenocarcinoma↗
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

[Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics by calcium channel blockers and calmodulin inhibitors].

One of the major causes of failure in cancer chemotherapy is the selection and proliferation of specific drug-resistant tumor cells during treatment. The mechanism of acquired resistance of tumor cells to some agents is related to intracellular drug accumulation and retention. For example, in vincristine (VCR)- and adriamycin (ADM)-resistant tumor cell sublines, these agents can be shown to enter the cell but are actively transported to the outside. This results in a relatively low intracellular level of drug and thus to low cytotoxicity. These observations suggest that if we could control the VCR- and ADM-efflux function of resistant tumor cells appropriately, then we could expect a reversal of acquired resistance to these drugs in drug resistant tumor cells. We found that calcium channel blockers and calmodulin inhibitors enhance the intracellular level of vincristine and adriamycin in tumor cells, especially in drug-resistant mouse and human tumor cells by inhibiting their outward transport. The approach using calcium modifiers has the following advantages. (1) Reversal of acquired resistance to vinca alkaloids and anthracyclic antibiotics can be attained. Calcium channel blockers, such as verapamil, diltiazem, nicardipine, niludipine and nimodipine, at doses of 30 to 125 mg/kg administered daily for 10 days with VCR (10-200 micrograms/mg) enhanced the chemotherapeutic effect of VCB (40-50% increase in life span) in P388/VCR-bearing mice. The calcium channel blockers also enhanced the therapeutic effect of ADM in ADM resistant P388 bearing mice. (2) The approach is also effective for the reversal of the inherent resistance of tumor cells to anticancer agents. Less sensitive tumor cells became more susceptible to VCR and the heterogeneity in drug sensitivity among tumor clones has been circumvented. (3) The approach with these calcium modifiers is also effective against other antitumor agents which are transported outside the cells by the similar mechanisms. As one of the mechanisms of cross-resistance is explained by the enhanced drug efflux from resistant tumor cells, antitumor agents which show cross-resistance to VCR and ADM become effective against resistant tumor cells by this approach. The mechanism of this approach is now under investigation. These calcium modifiers enhance the cellular level of antitumor agents by inhibiting their outward transport. The functions of cellular calcium and calmodulin in the membrane architecture and membrane functions might be involved in this process. Clinical evaluation is now under progress by using diltiazen, nicardipine and verapamil.

Animals↗
PubMed1984

High calcium content of pleiotropic drug-resistant P388 and K562 leukemia and Chinese hamster ovary cells.

The calcium content of pleiotropic drug-resistant tumor cells was estimated and compared with that of the parent tumor lines. P388 leukemia cells resistant to vincristine and Adriamycin contained more calcium (1.5- to 1.8-fold) in the cells and on the cell surface than the parent P388 cells. Similar results were obtained with human K562 myelogenous leukemia cells resistant to vincristine and also with Chinese hamster ovary cells resistant to colchicine. However, the calcium content of P388 cells resistant to 5-fluorouracil was almost the same as that of the parent P388 cells. The calmodulin content of pleiotropic resistant tumor lines and a 5-fluorouracil-resistant tumor line was almost the same as that of the corresponding parent lines. The isolated plasma membrane of K562 cells resistant to vincristine contained approximately 1.5-fold higher calcium than the parent cells. These results indicate that the higher cellular calcium content might be a characteristic phenotype of pleiotropic resistant tumor lines.

Animals↗
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

Purification and characterization of an amidohydrolase for N4-long-chain fatty acyl derivatives of 1-beta-D-arabinofuranosylcytosine from mouse liver microsomes.

N4-Long-chain fatty acyl-1-beta-D-arabinofuranosylcytosine amidohydrolase, a metabolizing enzyme for N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine with long-chain fatty acids, was purified from mouse liver microsomes. The purification was accomplished by solubilization of liver microsomes with Triton X-100, diethylaminoethyl cellulose chromatography, gel filtrations, hydroxyapatite chromatography, and concanavalin A:Sepharose chromatography. On sodium dodecyl sulfate:polyacrylamide gel electrophoresis, the purified enzyme preparation produced a single protein band with a molecular weight of 54,000. The enzyme had an optimal pH of 9.0, and the Michaelis constant for N4-palmitoyl-1-beta-D-arabinofuranosylcytosine was 67 microM. The thiols such as dithiothreitol or 2-mercaptoethanol stabilized the enzyme and stimulated its activity. p-Chloromercuribenzoate, N-ethylmaleimide, diisopropylfluorophosphate, and phenylmethylsulfonyl fluoride strongly inhibited the reaction. Bovine serum albumin markedly stimulated the enzyme activity, whereas detergents such as Triton X-100, deoxycholate, and sodium dodecyl sulfate had little effect. The enzyme did not require monovalent or divalent cations. Among the series of N4-acyl derivatives of 1-beta-D-arabinofuranosylcytosine with different chain lengths of acyl residues, the purified enzyme preferentially hydrolyzed the derivatives with long-chain fatty acids (C12 to C18), and N4-palmitoyl-1-beta-D-arabinofuranosylcytosine was the most susceptible. The purified enzyme was inactive on various N-acylamino acids, amides, oligopeptides, proteins, N-acylsphingosines (ceramides), triglyceride, lecithin, and lysolecithin. These results suggest that N4-long-chain fatty acyl-1-beta-D-arabinofuranosylcytosine amidohydrolase may be a new type of linear amidase.

Amidohydrolases↗